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Achromatopsia

, MSc, PhD, , MD, Dhabil, FEBO, , MSc, PhD, and , MD, PhD, Dhabil, FEBO.

Author Information

Initial Posting: ; Last Update: September 20, 2018.

Summary

Clinical characteristics.

Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination. All individuals with achromatopsia (achromats) have impaired color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middle-wavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). Most individuals have complete achromatopsia, with total lack of function of all three types of cones. Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning. The manifestations are similar to those of individuals with complete achromatopsia, but generally less severe.

Hyperopia is common in achromatopsia. Nystagmus develops during the first few weeks after birth followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time; both nystagmus and sensitivity to bright light may improve slightly. Although the fundus is usually normal, macular changes (which may show early signs of progression) and vessel narrowing may be present in some affected individuals. Defects in the macula are visible on optical coherence tomography.

Diagnosis/testing.

The diagnosis of achromatopsia is established in a proband through clinical and family history, examination for nystagmus, visual acuity testing, color vision assessment, and fundoscopic examination. If achromatopsia is suspected, additional testing may include optical coherence tomography, fundus autofluorescence, visual fields, and electroretinogram. Identification of biallelic pathogenic variants in ATF6, CNGA3, CNGB3, GNAT2, PDE6C, or PDE6H confirms the clinical diagnosis.

Management.

Treatment of manifestations: Dark or special filter glasses or red-tinted contact lenses to reduce photophobia and potentially improve visual acuity; low vision aids; preferential classroom seating for children; occupational aids.

Surveillance: Ophthalmologic examination every six to 12 months for children and every two to three years for adults.

Genetic counseling.

Achromatopsia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if the pathogenic variants have been identified in the family.

GeneReview Scope

Achromatopsia: Included Phenotypes 1
  • Complete achromatopsia (rod monochromatism, total color blindness)
  • Incomplete achromatopsia

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

Suggestive Findings

Achromatopsia should be suspected in individuals with the following typical clinical findings, additional testing, and family history.

Clinical findings

  • Pendular nystagmus
  • Increased sensitivity to light (photophobia)
  • Eccentric fixation
  • Reduced visual acuity
  • Reduced or complete lack of color discrimination
  • Small central scotoma
  • Fundus appearance: normal in many affected individuals, but can show subtle bilateral macular changes such as absence of the foveal reflex, pigment mottling, or narrowing of the retinal vessels. Frank atrophy of the retinal pigment epithelium (RPE) in the fovea can occur in older individuals.

Additional testing

Color vision tests. The color perception of individuals with achromatopsia (achromats) is unreliable; many achromats learn to associate certain colors with objects and to recognize some colors by discerning differences in brightness [Sharpe et al 1999]. In general, all achromats have anomalous (impaired) color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middle-wavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). The following results are found on standard testing for color vision:

  • Generally, no specific axis of color confusion is found on the Farnsworth Munsell 100-hue test.
  • An achromat axis (in which the constituent color chips are arranged according to their rod-perceived lightness) is characteristic for complete achromatopsia on both the saturated and desaturated versions of the Panel D-15 test.
  • The most important and diagnostic test is red-green color discrimination with the Rayleigh anomaloscope equation. Although a complete achromat can always fully color-match the spectral yellow primary to any mixture of the spectral red and green primaries, a brightness match is only possible to red primary-dominated mixtures.

Visual field testing. Small central scotomas can be demonstrated in some individuals by careful testing. However, unsteady fixation can make demonstration of a central scotoma difficult.

Electroretinogram (ERG)

  • Full-field ERG. The photopic response (including the 30-Hz flicker response) is absent or markedly diminished; the scotopic response is normal or mildly abnormal.
  • 15-Hz flicker ERG. A typical finding is absence of the cone-driven fast pathway response elicited by high flash intensities [Bijveld et al 2011].

Optical coherence tomography (OCT). A variable degree of foveal hypoplasia as well as disruption and/or loss of inner-/outer-segment junction of the photoreceptors and an attenuation of the RPE layer within the macular region can be observed at an early age [Genead et al 2011, Thomas et al 2011, Sundaram et al 2014, Lee et al 2015, Zobor et al 2017].

Fundus autofluorescence imaging shows missing or variable formation of foveal hypofluorescence or a larger lesion with a surrounding hyperautofluorescent ring and a central region of absent autofluorescence corresponding to the lesion area seen on OCT [Greenberg et al 2014, Kohl et al 2015].

Adaptive optics imaging shows remnant cone structure; however, the number and spatial distribution of the foveal cones are highly variable – the foveal cone mosaic ranges from a contiguously packed mosaic to a sparsely arranged collection of cones [Langlo et al 2016].

Family history is consistent with autosomal recessive inheritance.

Establishing the Diagnosis

The clinical diagnosis of achromatopsia is established in a proband with typical findings on clinical examination, additional testing, and family history (see Suggestive Findings). Identification of biallelic pathogenic variants in one of the six genes listed in Table 1 establishes the molecular diagnosis.

Molecular genetic testing approaches can include targeted analysis for the common CNGB3 variant c.1148delC, use of a multigene panel, or comprehensive genomic testing (typically exome sequencing):

  • Targeted analysis for the most common pathogenic variant c.1148delC in CNGB3 can be performed first in European populations or populations of European descent in the US, Canada, Australia, and New Zealand (see Molecular Genetics, CNGB3, Pathogenic variants).
  • A multigene panel that includes ATF6, CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing does not require the clinician to determine which gene[s] are likely involved. Exome sequencing is most commonly used; genome sequencing can also be used.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Achromatopsia

Gene 1Proportion of Achromatopsia Attributed to Pathogenic Variants in This Gene 2 (Population)Proportion of Pathogenic Variants 3 Detectable by Test Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
ATF61.5%15/15 6None reported 7
CNGA35%-33% (European)
84% (Israeli & Palestinian) 8
80% (Chinese) 9
~100% 10None reported 7
CNGB360% (European)
16% (Israeli & Palestinian) 11
~95% 127 distinct deletions in 7 families; 3 duplications in 10 families 13
GNAT21.8%~99%3 families 14
PDE6C2.5% 15All reported 16None reported 7
PDE6H0.1%See footnote 17None reported 7
Unknown10%-25% 18NA
1.
2.

Mayer et al [2017] unless otherwise noted.

3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.
7.

Larger deletions, insertions, or duplications have either not been reported or are confined to single reports or families [Rosenberg et al 2004]. Consequently, the prevalence and detection rate for such pathogenic variants cannot be estimated.

8.
9.
10.
11.
12.

Of 163 individuals with pathogenic variants in CNGB3, 105 (64%) were homozygotes for c.1148delC, 44 (27%) were compound heterozygotes, and in 14 (9%) only one pathogenic variant was identified [Mayer et al 2017].

13.
14.

Rosenberg et al [2004]; S Kohl, unpublished data

15.
16.
17.

A single nonsense variant has been reported in three families [Kohl et al 2012, Pedurupillay et al 2016].

18.

Clinical Characteristics

Clinical Description

Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma (which is often difficult to demonstrate), eccentric fixation, and reduced or complete lack of color discrimination. Hyperopia is common. Nystagmus develops during the first few weeks after birth and is followed by increased sensitivity to bright light.

Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time, but both nystagmus and sensitivity to bright light may improve slightly. The fundus is usually normal, but macular changes and vessel narrowing may be present in some individuals, and optical coherence tomography (OCT) reveals macular changes that can progress with time [Thomas et al 2012].

Most individuals have complete achromatopsia, in which the symptoms can be explained by a total lack of function of all three types of cone (i.e., photopic) photoreceptors of the eye, with all visual functions being mediated by the rod (i.e., scotopic) photoreceptors.

Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning along with the rods. The symptoms are similar to those of individuals with complete achromatopsia but generally less severe [Sharpe et al 1999]. Color discrimination ranges from well preserved to severely impaired; photophobia is usually absent; visual acuity is better preserved than in complete achromatopsia.

Phenotype Correlations by Gene

Complete achromatopsia. The majority of individuals with biallelic pathogenic variants in ATF6, CNGA3, CNGB3, GNAT2, and PDE6C have complete achromatopsia with similar clinical features. A significant genotype-phenotype correlation cannot be observed; however, individuals with ATF6-associated achromatopsia usually have a poorly formed or absent foveal pit.

Incomplete achromatopsia

Nomenclature

The complete form of achromatopsia is also referred to as rod monochromacy (monochromatism), complete (or total) color blindness (OMIM 216900), day blindness (hemeralopia), or "Pingelapese blindness." Clinically, it is known as typical, complete achromatopsia or complete achromatopsia with reduced visual acuity.

The incomplete form of achromatopsia is also known clinically as atypical, incomplete achromatopsia or incomplete achromatopsia with reduced visual acuity.

Prevalence

Achromatopsia is a rare disorder with an estimated prevalence of fewer than 1:30,000 [Sharpe et al 1999].

Parental consanguinity is common in certain geographic regions. On the island of Pingelap in the eastern Caroline Islands in Micronesia, the prevalence of achromatopsia is between 4% and 10%, secondary to the founder variant p.Ser435Phe in CNGB3 [Sharpe et al 1999].

Differential Diagnosis

Achromatopsia is readily recognized by its characteristic features (see Suggestive Findings). Conditions to consider in the differential diagnosis are congenital nystagmus (as nystagmus is usually one of the first manifestations) and cerebral achromatopsia or dyschromatopsia, which is associated with severe or total color vision deficits and can arise adventitiously after brain fever, cortical trauma, or cerebral infarction, especially involving lesions to the ventral occipital cortex [Bouvier & Engel 2006].

Inherited retinal dystrophies that may be confused with achromatopsia are summarized in Table 3.

Table 3.

Inherited Retinal Dystrophies to Consider in the Differential Diagnosis of Achromatopsia

DisorderGene(s)MOIOverlapping Clinical FeaturesDistinguishing Clinical FeaturesComments
Blue-cone monochromatism 1 (OMIM 303700)OPN1LW; OPN1MW 2XL 3
  • Severely ↓ visual acuity
  • Eccentric fixation
  • ± Infantile nystagmus
  • No obvious fundus abnormalities
  • Poor or no color discrimination 4
In blue-cone monochromatism:
  • Peak of photopic luminosity function is near 440 nm (the peak sensitivity of the S cones), not 507 nm (the peak sensitivity of the rods).
  • Mostly males are affected.
  • A special 4-color plate test or a 2-color filter test can clinically distinguish blue-cone monochromats from achromats (rod monochromats).
  • Cone ERG responses can be elicited by presenting blue flashes on a yellow background (because the S cones are functioning in addition to the rods).
Hereditary red-green color vision defects (OMIM 303800, 303900)OPN1LW, OPN1MWXLColor vision defects 5In hereditary red-green color vision defects:
  • Absence of ophthalmologic or other associated clinical abnormalities
  • Most individuals w/protanomalous & deuteranomalous color vision defects (i.e., anomalous trichromats) have no major problems in naming colors.
  • Mostly males are affected.
  • Clinical chart tests widely used to detect red-green color vision defects include Ishihara plates & the American Optical HRR pseudoisochromatic plates.
  • Definitive classification of color vision defects known as protanopia, deuteranopia, protanomaly, & deuteranomaly requires use of anomaloscope, which involves color matching.
Tritan and yellow-blue defects
(OMIM 190900)
OPN1SWADColor confusionIn tritan & yellow-blue defects: color confusion is limited to blues & greens. 6Other non-congenital yellow-blue deficits (similar in some ways to tritan defects) may result from aging or disorders of choroid, pigment epithelium, retina, or optic nerve (e.g., optic atrophy type 1); they are usually progressive & have other related signs; e.g. associated visual acuity defects. 7
Cone / cone-rod dystrophies 8ABCA4, AIPL1, CABP4, CNNM4, CDHR1, GUCY2D, KCNV2, RAB28, RPGRIP1AD, AR
  • Cone function may be normal at birth.
  • Typical symptoms (↓ visual acuity, photophobia, ↑ sensitivity to glare, abnormal color vision) appear later. 9
  • Age of onset of vision loss may be as early as childhood or as late as 7th decade.
  • Dark-adapted rod thresholds may be elevated. 10
Disease progression occurs in cone dystrophy & typically not in achromatopsia.
  • Differentiating between achromatopsia & cone dystrophy can be difficult, particularly in individuals w/early-childhood onset.
  • Best clinical discriminator is disease progression.
Leber congenital amaurosis (LCA)AIPL1
CABP4
CEP290
GUCY2D
RPGRIP1
AR
  • Infantile nystagmus
  • Photophobia
  • Severely reduced visual acuity
  • No obvious fundus abnormalities
  • Poor or no color discrimination
Night blindness & progression occur in LCA.In very young individuals
Bradyopsia; delayed cone adaptationRGS9
  • Prolonged electroretinal response suppression leading to difficulties adjusting to changes in luminance
  • Normal to subnormal visual acuity
  • Photophobia
Alström syndrome 11ALMS1AR
  • Infantile nystagmus
  • Photophobia
  • Severely reduced visual acuity
  • Poor or no color discrimination
Possible additional findings: cardiomyopathy, kidney failure, obesity, sensorineural hearing loss, diabetesIn young individuals

ERG = electroretinogram

1.

Blue-cone monochromacy may also be referred to as S-cone monochromacy or X-chromosome-linked achromatopsia.

2.

The dysfunction of the L (red) and M (green) cones is caused by pathogenic variants leading to the loss of the X-linked red (OPN1LW) and green (OPN1MW) opsin gene array, hybrid gene formation and/or inactivating variants, or by deletions affecting the locus control region, a critical region that regulates the expression of the red/green (OPN1LW/OPN1MW) gene array.

3.

Blue-cone monochromacy affects mostly males.

4.
5.

Some males with mildly defective red-green color vision may not be aware of it until they are tested. Among individuals of northern European origin, about 8% of males and 0.5% of females have red-green color vision defects; these defects are less frequent among males of African (3%-4%) or Asian (3%) origin.

6.

Often referred to as yellow-blue disorders, although the color confusion is typically between blues & greens, tritan defects affect the S (blue) cones.

7.
8.

See Glöckle et al [2014], Weisschuh et al [2016], Carss et al [2017] for genes identified in patients misdiagnosed as having achromatopsia.

9.
10.
11.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with achromatopsia, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

  • Standard clinical ophthalmologic evaluation and testing with attention to visual acuity and use of spectacles and/or contact lenses to achieve the best possible corrected visual acuity
  • Color vision evaluation
  • Consultation with a clinical geneticist and/or genetic counselor as treatment could be possible in the near future (see Therapies Under Investigation)

Treatment of Manifestations

Dark or special filter glasses or red-tinted contact lenses reduce photophobia and may improve visual acuity.

Low vision aids include high-powered magnifiers for reading as well as digital/electronic devices.

Children with achromatopsia should have preferential seating in the classroom (i.e., in the front to benefit maximally from magnifying devices and away from windows to reduce the effects of glare on vision).

Extensive information about learning and occupational aids is available from the Achromatopsia Network (www.achromat.org).

Surveillance

Ophthalmologic examination is indicated:

  • Every six to 12 months in children to monitor changes in refraction in order to achieve the best possible corrected visual acuity;
  • Every two to three years in adults.

Agents/Circumstances to Avoid

To avoid additional light damage to the retina, it is recommended that individuals wear appropriate protective (dark) glasses in bright light.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

In July 2012 a Phase I/II clinical trial (NCT01846052) investigating the therapeutic effects and safety of an intraocular implant releasing ciliary neurotrophic factor (CNTF) in individuals with CNGB3-related achromatopsia was started. No objectively measurable enhancement of cone function was found by assessments of visual acuity, mesopic increment sensitivity threshold, photopic electroretinogram, or color hue discrimination. Subjectively, individuals reported beneficial changes of visual function in the treated eyes, including reduced light sensitivity and aversion to bright light, but slowed adaptation to darkness, consistent with CNTF action on rod photoreceptors [Zein et al 2014].

Several interventional Phase I/II clinical safety and efficacy trials for gene replacement therapy using viral AAV vectors for CNGA3-related achromatopsia (NCT02610582, NCT02935517) and CNGB3-related achromatopsia (NCT02599922, NCT03278873, NCT03001310) are currently running and recruiting patients.

In addition, clinical observational trials have been or are recruiting individuals for clinical assessment to establish the natural history of achromatopsia (NCT02435940, NCT01846052).

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Achromatopsia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one achromatopsia-related pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with achromatopsia are obligate heterozygotes (carriers) for an achromatopsia-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an achromatopsia-related pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the achromatopsia-related pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the achromatopsia-related pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for achromatopsia are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B.

OMIM Entries for Achromatopsia (View All in OMIM)

139340GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-TRANSDUCING ACTIVITY POLYPEPTIDE 2; GNAT2
216900ACHROMATOPSIA 2; ACHM2
262300ACHROMATOPSIA 3; ACHM3
600053CYCLIC NUCLEOTIDE-GATED CHANNEL, ALPHA-3; CNGA3
600827PHOSPHODIESTERASE 6C, cGMP-SPECIFIC, CONE, ALPHA-PRIME; PDE6C
601190PHOSPHODIESTERASE 6H, cGMP-SPECIFIC, CONE, GAMMA; PDE6H
605080CYCLIC NUCLEOTIDE-GATED CHANNEL, BETA-3; CNGB3
605537ACTIVATING TRANSCRIPTION FACTOR 6; ATF6
610024RETINAL CONE DYSTROPHY 3A; RCD3A
613093CONE DYSTROPHY 4; COD4
613856ACHROMATOPSIA 4; ACHM4
616517ACHROMATOPSIA 7; ACHM7

Molecular Genetic Pathogenesis

CNGB3, CNGA3, PDE6C, GNAT2, and PDE6H are all expressed in the cone photoreceptor and are crucial for cone phototransduction:

  • Light-excited cone visual pigment molecules induce the exchange of GDP to GTP on the transducin alpha subunit (GNAT2) and its release from the inhibitory beta/gamma subunits.
  • The activated GTP-transducin then binds and activates the alpha' subunit of the retinal cone photoreceptor phosphodiesterase (PDE6C) by retracting the inhibitory gamma subunit (PDE6H).
  • Retinal cone photoreceptor PDE6C hydrolyzes cGMP, reducing its intracellular concentration and causing closure of the heterotetrameric cGMP-gated cation channels (CNGA3 and CNGB3) and, subsequently, membrane hyperpolarization [Lamb & Pugh 2006].

Transducin thus mediates the first step, the phosphodiesterase the intermediate, and the cGMP-gated channel represents the final step in the phototransduction cascade.

In contrast, the most recently identified ACHM-related gene, ATF6, encodes a ubiquitously expressed transmembrane transcription factor known for its function in the ATF6 unfolded protein response pathway [Walter & Ron 2011, Wang & Kaufman 2012, Kohl et al 2015]. How and why pathogenic variants in this ubiquitously expressed gene result solely in cone dysfunction is to date unknown.

ATF6

Gene structure. ATF consists of 16 coding exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Thirteen different pathogenic variants have been reported in 15 families [Ansar et al 2015, Kohl et al 2015, Xu et al 2015, Carss et al 2017, Skorczyk-Werner et al 2017]. Nine of the 13 are nonsense variants, splice site variants, small insertions, and deletions. Only four missense variants have been reported.

Six individuals (from 2 unrelated families of Irish/British descent) who are homozygous for c.970C>T have been identified; the families were shown to have a common haplotype of 0.7 Mb suggestive of a founder variant [Kohl et al 2015]. Another pathogenic variant, c.1533+1G>C, was observed recurrently in four French Canadian families, also suggesting a founder variant in this population [Kohl et al 2015, Xu et al 2015].

Table 4.

ATF6 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.970C>Tp.Arg324CysNM_007348​.3
NP_031374​.2
c.1533+1G>CSee footnote 1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Two cDNAs were identified, one with partial intron retention and one with exon skipping [Kohl et al 2015].

Normal gene product. ATF6 encodes a 670-amino-acid, ubiquitously expressed 90-kd ER stress-regulated transmembrane transcription factor known for its function in one of three unfolded protein response pathways (i.e., ATF6 pathway). It is required for ER stress response and transcriptional induction from ER stress-response elements (ERSEs). On induction of ER stress, the cytosolic ~400-residue N-terminal portion of ATF6 (N-ATF6) is released. N-ATF6 possesses the transcriptional activation domain, the bZIP domain, the DNA-binding domain, and nuclear localization signals. It translocates to the nucleus, where it interacts with several other proteins to form an ERSE-binding complex that is responsible for the induction of ER stress genes (ERSGs) [Walter & Ron 2011, Wang & Kaufman 2012].

Abnormal gene product. Most pathogenic missense variants result in loss of protein function. One missense variant, p.Arg324Cys, localizes to the basic region of the bZIP domain, affecting an arginine residue that is conserved not only among transcription factors of the ATF family but also in those of the AP-1 family, severely impairing ATF6 transcriptional activity [Kohl et al 2015]. The p.Arg324Cys variant was functionally characterized in detail and shown to impair transcriptional activity [Kohl et al 2015, Chiang et al 2017].

Other missense changes have been studied and divided into class I, 2, or 3:

  • Class 1. Disease-associated ATF6 missense variants that result in impaired ER-to-Golgi trafficking and diminished regulated intramembrane proteolysis and transcriptional activity
  • Class 2. Disease-associated ATF6 missense variants that retain the entire ATF6 cytosolic domain with fully intact transcriptional activity and constitutive induction of downstream target genes, even in the absence of ER stress
  • Class 3. ATF6 missense variants with complete loss of transcriptional activity because of absent or defective bZIP domains

Primary fibroblasts from patients with class 1 or class 3 ATF6 pathogenic variants show increased cell death in response to ER stress [Chiang et al 2017].

Of note, the Atf6 knockout mouse model does not recapitulate the human achromatopsia phenotype [Kohl et al 2015].

CNGA3

Gene structure. CNGA3 consists of eight coding exons [Wissinger et al 2001]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 150 different pathogenic variants have been associated with ACHM [Kohl et al 1998, Wissinger et al 2001, Johnson et al 2004, Tränkner et al 2004, Nishiguchi et al 2005, Varsányi et al 2005, Ahuja et al 2008, Koeppen et al 2008, Reuter et al 2008, Koeppen et al 2010, Thiadens et al 2010, Genead et al 2011, Vincent et al 2011]. The vast majority of pathogenic variants are missense (~80%). Only a few nonsense variants, insertions, and deletions have been observed.

Normal gene product. CNGA3 encodes the cyclic nucleotide-gated cation channel alpha 3 (the alpha subunit of the cone photoreceptor cGMP-gated cation channel [CNG]). CNGA3 has 694 amino acids and a predicted weight of 78.8 kd. An alternatively spliced exon that extends the open reading frame by an additional 55 amino acids has been reported [Wissinger et al 2001]. Alpha subunits on CNG channels are able to form functional homo-oligomeric channels, yet their biophysical properties differ from those of heteromeric native CNG channels consisting of three alpha subunits and one beta subunit.

Abnormal gene product. Functional analysis has shown that in many cases channel function is strongly impaired or completely absent. The pathogenic missense variants mostly affect amino acid residues that are highly conserved among the members of the CNG channel family, and cluster at structural and functional domains including the cGMP-binding domain [Wissinger et al 2001, Faillace et al 2004, Patel et al 2005, Koeppen et al 2008, Reuter et al 2008].

Some pathogenic variants in the pore region and the cGMP binding domain are associated with incomplete achromatopsia. These abnormal proteins can form functional channels, but with grossly altered properties, including altered affinity for cGMP and/or cAMP, and changes in the gating properties of the cone CNG channels, like Ca2+ blockage and permeation [Tränkner et al 2004, Liu & Varnum 2005, Reuter et al 2008, Koeppen et al 2010].

Animal models have helped to clarify the underlying pathogenic mechanisms:

  • Mouse. Cnga3(-/-) mice show absence of cone function, a decrease in the number of cones in the retina, and morphologic abnormalities of the remaining cones. Cnga3(-/-) cones fail to transport opsin into the outer segment and downregulate various proteins of the phototransduction cascade. Apoptotic cell death is induced; however, loss of Cnga3 does not appear to affect the transcription of other cone-specific genes [Biel et al 1999, Michalakis et al 2005]. Gene therapy has been successfully tested in these mouse models and shown to restore cone-mediated vision [Michalakis et al 2012].
  • Sheep. Lambs with congenital day blindness are homozygous for the pathogenic nonsense variant FN377574:c.706C>T (p.Arg236Ter) in the ovine CNGA3 and serve as animal models for studying human achromatopsia and evaluating gene therapeutic approaches [Reicher et al 2010, Banin et al 2015].

CNGB3

Gene structure. CNGB3 consists of 18 coding exons [Kohl et al 2000]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 125 different pathogenic variants have been reported [Kohl et al 2000, Sundin et al 2000, Rojas et al 2002, Johnson et al 2004, Michaelides et al 2004, Okada et al 2004, Kohl et al 2005, Nishiguchi et al 2005, Varsányi et al 2005, Khan et al 2007, Wiszniewski et al 2007, Thiadens et al 2009b, Azam et al 2010, Mayer et al 2017]. The vast majority are pathogenic nonsense variants, frameshift deletions and insertions, and putative splice site variants. Only a few pathogenic missense variants (~10%) have been observed.

One, resulting in the p.Ser435Phe mutated protein, causes "Pingelapese blindness" in achromats originating from the island of Pingelap in Micronesia [Kohl et al 2000, Sundin et al 2000].

The recurrent single base-pair deletion c.1148delC is the most common pathogenic variant underlying achromatopsia worldwide, accounting for approximately 70% of all CNGB3 disease-causing alleles and approximately 40% of all achromatopsia-associated alleles. The c.1148delC deletion results from a founder effect [Wiszniewski et al 2007].

Table 5.

CNGB3 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1148delCp.Thr383IlefsTer13NM_019098​.3
NP_061971​.3
c.1304C>Tp.Ser435Phe

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. CNGB3 encodes for cyclic nucleotide-gated cation channel beta 3 (the beta subunit of the cone photoreceptor cGMP-gated cation channel). CNGB3 is 809 amino acids long. The beta subunits are not able to form functional homo-oligomeric channels; they are therefore thought to be modulatory subunits. Functional cone CNG channels consist of three alpha subunits and one beta subunit.

Abnormal gene product. Functional analysis has shown that in many cases channel function is strongly impaired or completely absent [Peng et al 2003, Okada et al 2004, Bright et al 2005]. However, certain disease-associated CNGB3 variants in the subunit are apparent gain-of-function variants [Okada et al 2004, Bright et al 2005]. Expression of human wild type CNGA3 and mutated CNGB3 containing the Pingelapese blindness-associated p.Ser435Phe variant generated functional heteromeric channels that exhibited an increase in apparent affinity for both cAMP and cGMP and changes in the pore properties of the channel compared with wild type heteromeric channels.

Animal models have helped to clarify the underlying pathogenic mechanisms. Two naturally occurring CNGB3-null canine models, Alaskan malamute and German shorthaired pointer, have been identified [Sidjanin et al 2002]. In the Alaskan malamute, cone-degenerate pups develop day blindness and photophobia. Cone function, detectable on electroretinogram in very young affected pups, begins to fail at a few weeks' age and is undetectable in mature affected dogs. Adult affected retinas lack all cones. The first gene therapy studies in these animals showed restoration of cone-mediated vision, but the success was dependent on the age of intervention [Komáromy et al 2010].

GNAT2

Gene structure. GNAT2 consists of eight coding exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Sixteen different disease-associated variants (nonsense variant, deletions and/or insertions, one large deletion of exon 4, and a variant c.461+24G>A activating a cryptic splice site and resulting in frameshift and PTC) have been described to date [Aligianis et al 2002, Kohl et al 2002, Michaelides et al 2003, Piña et al 2004, Rosenberg et al 2004, Ouechtati et al 2011, Langlo et al 2016, Bryant et al 2017, Carss et al 2017, Taylor et al 2017, Ueno et al 2017].

Table 6.

GNAT2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.461+24G>A--NM_005272​.3
NP_005263​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. GNAT2 encodes for guanine nucleotide-binding protein G(t), alpha-2 subunit (the cone-specific alpha subunit of transducin), a heterotrimeric G protein that couples to the cone photopigments. The protein is 354 amino acids long.

Abnormal gene product. The majority of pathogenic variants result in loss of protein function [Cai et al 2001]. The c.461+24G>A variant results in leaky aberrant splicing, resulting in a milder phenotype described as incomplete achromatopsia or oligo-cone trichromacy [Rosenberg et al 2004].

Animal models have helped to clarify the underlying pathogenic mechanisms.

An achromatopsia mouse model is homozygous for the murine Gnat2 pathogenic variant NM_008141.3:c.598G>A (p.Asp200Asn) in exon 6 (also referred to as the cpfl3 variant) [Chang et al 2006]. Homozygous mice have poor cone-mediated responses on electroretinogram (ERG) at three weeks that become undetectable by nine months. Microscopy of the retina reveals progressive vacuolization of the photoreceptor outer segments. Immunocytochemistry with cone-specific markers shows progressive loss of labeling for Gnat2 protein, but the cone outer segments in the oldest mice examined remain intact [Chang et al 2006].

PDE6C

Gene structure. PDE6C consists of 22 coding exons [Piriev et al 1995]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 50 different pathogenic variants in PDE6C have been described; they include missense variants, nonsense variants, small indels, and variants affecting splicing [Chang et al 2009, Thiadens et al 2009b, Grau et al 2011, Huang et al 2013, Weisschuh et al 2018].

Normal gene product. PDE6C encodes PDE6C, the phosphodiesterase 6C, cGMP-specific, cone, alpha-prime. This alpha' subunit of the cone-specific phosphodiesterase consists of 858 amino acids.

Abnormal gene product. Disease-associated variants result in markedly reduced to completely absent PDE6C enzymatic activity [Chang et al 2009, Grau et al 2011].

Animal models have helped to clarify the underlying pathogenic mechanisms. The cone photoreceptor function loss 1 (cpfl1) mouse mutant is a model for Pde6c-related achromatopsia [Chang et al 2009], which has a 116-bp insertion between exons 4 and 5 (NM_001170959.1:c.864_865ins116) and an additional 1-bp deletion in exon 7 (NM_001170959.1:c.1042delT) in cis (on the same allele). The phenotype can be easily typed by ERG as early as age three weeks. Histology of cpfl1 mouse retinae revealed grossly normal morphology and layering. However, as early as age three weeks, there was vacuolization of a small subset of cells in the photoreceptor layer with subsequent rapid, progressive depletion of cone photoreceptors. Loss of cones progresses, such that very few were detected in retinal sections of five-month-old animals [Chang et al 2009].

PDE6H

Gene structure. PDE6H consists of only three coding exons [Shimizu-Matsumoto et al 1996]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Originally the single homozygous pathogenic nonsense variant c.35C>G in PDE6H was described in three affected individuals from two independent families originating from Belgium and the Netherlands [Kohl et al 2012]. Recently, two Pakistani brothers were shown to be homozygous for the same pathogenic variant [Pedurupillay et al 2016].

Table 7.

PDE6H Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.35C>Gp.Ser12TerNM_006205​.2
NP_006196​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. PDE6H encodes phosphodiesterase 6H, cGMP-specific, cone, gamma; PDE6H, the inhibitory gamma subunit of the cone photoreceptor phosphodiesterase. PDE6H consists of only 83 amino acids.

Abnormal gene production. The sole PDE6H nonsense variant is predicted to result in complete loss of function of PDE6H either by degradation of the mRNA by nonsense-mediated decay or the truncation of the protein [Kohl et al 2012].

Of note, the Pde6h knockout mouse model does not recapitulate the human achromatopsia phenotype [Brennenstuhl et al 2015].

References

Literature Cited

  • Aboshiha J, Luong V, Cowing J, Dubis AM, Bainbridge JW, Ali RR, Webster AR, Moore AT, Fitzke FW, Michaelides M. Dark-adaptation functions in molecularly confirmed achromatopsia and the implications for assessment in retinal therapy trials. Invest Ophthalmol Vis Sci. 2014;55:6340–9. [PMC free article: PMC4193759] [PubMed: 25168900]
  • Ahuja Y, Kohl S, Traboulsi EI. CNGA3 mutations in two United Arab Emirates families with achromatopsia. Mol Vis. 2008;14:1293–7. [PMC free article: PMC2464613] [PubMed: 18636117]
  • Aligianis IA, Forshew T, Johnson S, Michaelides M, Johnson CA, Trembath RC, Hunt DM, Moore AT, Maher ER. Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2). J Med Genet. 2002;39:656–60. [PMC free article: PMC1735242] [PubMed: 12205108]
  • Ansar M, Santos-Cortez RL, Saqib MA, Zulfiqar F, Lee K, Ashraf NM, Ullah E, Wang X, Sajid S, Khan FS, Amin-Ud-Din M, Smith JD, Shendure J, Bamshad MJ, Nickerson DA, Hameed A, Riazuddin S, Ahmed ZM, Ahmad W, Leal SM, et al. Mutation of ATF6 causes autosomal recessive achromatopsia. Hum Genet. 2015;134:941–50. [PMC free article: PMC4529463] [PubMed: 26063662]
  • Azam M, Collin RW, Shah ST, Shah AA, Khan MI, Hussain A, Sadeque A, Strom TM, Thiadens AA, Roosing S, den Hollander AI, Cremers FP, Qamar R. Novel CNGA3 and CNGB3 mutations in two Pakistani families with achromatopsia. Mol Vis. 2010;16:774–81. [PMC free article: PMC2862243] [PubMed: 20454696]
  • Banin E, Gootwine E, Obolensky A, Ezra-Elia R, Ejzenberg A, Zelinger L, Honig H, Rosov A, Yamin E, Sharon D, Averbukh E, Hauswirth WW, Ofri R. Gene augmentation therapy restores retinal function and visual behavior in a sheep model of CNGA3 achromatopsia. Mol Ther. 2015;23:1423–33. [PMC free article: PMC4817879] [PubMed: 26087757]
  • Biel M, Seeliger M, Pfeifer A, Kohler K, Gerstner A, Ludwig A, Jaissle G, Fauser S, Zrenner E, Hofmann F. Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3. Proc Natl Acad Sci U S A. 1999;96:7553–7. [PMC free article: PMC22124] [PubMed: 10377453]
  • Bijveld MM, Riemslag FC, Kappers AM, Hoeben FP, van Genderen MM. An extended 15 Hz ERG protocol (2): data of normal subjects and patients with achromatopsia, CSNB1, and CSNB2. Doc Ophthalmol. 2011;123:161–72. [PubMed: 21947599]
  • Bouvier SE, Engel SA. Behavioral deficits and cortical damage loci in cerebral achromatopsia. Cereb Cortex. 2006;16:183–91. [PubMed: 15858161]
  • Brennenstuhl C, Tanimoto N, Burkard M, Wagner R, Bolz S, Trifunovic D, Kabagema-Bilan C, Paquet-Durand F, Beck SC, Huber G, Seeliger MW, Ruth P, Wissinger B, Lukowski R. Targeted ablation of the Pde6h gene in mice reveals cross-species differences in cone and rod phototransduction protein isoform inventory. J Biol Chem. 2015;290:10242–55. [PMC free article: PMC4400339] [PubMed: 25739440]
  • Bright SR, Brown TE, Varnum MD. Disease-associated mutations in CNGB3 produce gain of function alterations in cone cyclic nucleotide-gated channels. Mol Vis. 2005;11:1141–50. [PubMed: 16379026]
  • Bryant L, Lozynska O, Maguire AM, Aleman TS, Bennett J. Prescreening whole exome sequencing results from patients with retinal degeneration for variants in genes associated with retinal degeneration. Clin Ophthalmol. 2017;12:49–63. [PMC free article: PMC5749571] [PubMed: 29343940]
  • Cai K, Itoh Y, Khorana HG. Mapping of contact sites in complex formation between transducin and light-activated rhodopsin by covalent crosslinking: use of a photoactivatable reagent. Proc Natl Acad Sci U S A. 2001;98:4877–82. [PMC free article: PMC33131] [PubMed: 11320237]
  • Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, Megy K, Grozeva D, Dewhurst E, Malka S, Plagnol V, Penkett C, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, Carmichael J, Chitre M, Henderson RHH, Hurst J, MacLaren RE, Murphy E, Paterson J, Rosser E, Thompson DA, Wakeling E, Ouwehand WH, Michaelides M, Moore AT, Webster AR, Raymond FL, et al. Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am J Hum Genet. 2017;100:75–90. [PMC free article: PMC5223092] [PubMed: 28041643]
  • Chang B, Dacey MS, Hawes NL, Hitchcock PF, Milam AH, Atmaca-Sonmez P, Nusinowitz S, Heckenlively JR. Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2. Invest Ophthalmol Vis Sci. 2006;47:5017–21. [PubMed: 17065522]
  • Chang B, Grau T, Dangel S, Hurd R, Jurklies B, Sener EC, Andreasson S, Dollfus H, Baumann B, Bolz S, Artemyev N, Kohl S, Heckenlively J, Wissinger B. A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. Proc Natl Acad Sci U S A. 2009;106:19581–6. [PMC free article: PMC2780790] [PubMed: 19887631]
  • Chiang WC, Chan P, Wissinger B, Vincent A, Skorczyk-Werner A, Krawczyński MR, Kaufman RJ, Tsang SH, Héon E, Kohl S, Lin JH. Achromatopsia mutations target sequential steps of ATF6 activation. Proc Natl Acad Sci U S A. 2017;114:400–5. [PMC free article: PMC5240680] [PubMed: 28028229]
  • Faillace MP, Bernabeu RO, Korenbrot JI. Cellular processing of cone photoreceptor cyclic GMP-gated ion channels: a role for the S4 structural motif. J Biol Chem. 2004;279:22643–53. [PubMed: 15024024]
  • Genead MA, Fishman GA, Rha J, Dubis AM, Bonci DM, Dubra A, Stone EM, Neitz M, Carroll J. Photoreceptor structure and function in patients with congenital achromatopsia. Invest Ophthalmol Vis Sci. 2011;52:7298–308. [PMC free article: PMC3183969] [PubMed: 21778272]
  • Glöckle N, Kohl S, Mohr J, Scheurenbrand T, Sprecher A, Weisschuh N, Bernd A, Rudolph G, Schubach M, Poloschek C, Zrenner E, Biskup S, Berger W, Wissinger B, Neidhardt J. Eur J Hum Genet. 2014;22:99–104. Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies. [PMC free article: PMC3865404] [PubMed: 23591405]
  • Grau T, Artemyev NO, Rosenberg T, Dollfus H, Haugen OH, Cumhur Sener E, Jurklies B, Andreasson S, Kernstock C, Larsen M, Zrenner E, Wissinger B, Kohl S. Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia. Hum Mol Genet. 2011;20:719–30. [PMC free article: PMC3269206] [PubMed: 21127010]
  • Greenberg JP, Sherman J, Zweifel SA, Chen RW, Duncker T, Kohl S, Baumann B, Wissinger B, Yannuzzi LA, Tsang SH. Spectral-domain optical coherence tomography staging and autofluorescence imaging in achromatopsia. JAMA Ophthalmol. 2014;132:437–45. [PMC free article: PMC4423754] [PubMed: 24504161]
  • Holopigian K, Greenstein VC, Seiple W, Hood DC, Carr RE. Rod and cone photoreceptor function in patients with cone dystrophy. Invest Ophthalmol Vis Sci. 2004;45:275–81. [PubMed: 14691184]
  • Huang L, Zhang Q, Li S, Guan L, Xiao X, Zhang J, Jia X, Sun W, Zhu Z, Gao Y, Yin Y, Wang P, Guo X, Wang J, Zhang Q. Exome sequencing of 47 Chinese families with cone-rod dystrophy: mutations in 25 known causative genes. PLoS One. 2013;8:e65546. [PMC free article: PMC3679152] [PubMed: 23776498]
  • Johnson S, Michaelides M, Aligianis IA, Ainsworth JR, Mollon JD, Maher ER, Moore AT, Hunt DM. Achromatopsia caused by novel mutations in both CNGA3 and CNGB3. J Med Genet. 2004;41:e20. [PMC free article: PMC1735666] [PubMed: 14757870]
  • Khan NW, Wissinger B, Kohl S, Sieving PA. CNGB3 achromatopsia with progressive loss of residual cone function and impaired rod-mediated function. Invest Ophthalmol Vis Sci. 2007;48:3864–71. [PubMed: 17652762]
  • Koeppen K, Reuter P, Kohl S, Baumann B, Ladewig T, Wissinger B. Functional analysis of human CNGA3 mutations associated with colour blindness suggests impaired surface expression of channel mutants A3(R427C) and A3(R563C). Eur J Neurosci. 2008;27:2391–401. [PubMed: 18445228]
  • Koeppen K, Reuter P, Ladewig T, Kohl S, Baumann B, Jacobson SG, Plomp AS, Hamel CP, Janecke AR, Wissinger B. Dissecting the pathogenic mechanisms of mutations in the pore region of the human cone photoreceptor cyclic nucleotide-gated channel. Hum Mutat. 2010;31:830–9. [PubMed: 20506298]
  • Kohl S, Baumann B, Broghammer M, Jägle H, Sieving P, Kellner U, Spegal R, Anastasi M, Zrenner E, Sharpe LT, Wissinger B. Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Hum Mol Genet. 2000;9:2107–16. [PubMed: 10958649]
  • Kohl S, Baumann B, Rosenberg T, Kellner U, Lorenz B, Vadala M, Jacobson SG, Wissinger B. Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet. 2002;71:422–5. [PMC free article: PMC379175] [PubMed: 12077706]
  • Kohl S, Coppieters F, Meire F, Schaich S, Roosing S, Brennenstuhl C, Bolz S, van Genderen MM, Riemslag FCC, Lukowski R, den Hollander AI, Cremers FPM, De Baere E, Hoyng CB, Wissinger B, et al. A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia. Am J Hum Genet. 2012;91:527–32. [PMC free article: PMC3511981] [PubMed: 22901948]
  • Kohl S, Marx T, Giddings I, Jägle H, Jacobson SG, Apfelstedt-Sylla E, Zrenner E, Sharpe LT, Wissinger B. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet. 1998;19:257–9. [PubMed: 9662398]
  • Kohl S, Varsanyi B, Antunes GA, Baumann B, Hoyng CB, Jägle H, Rosenberg T, Kellner U, Lorenz B, Salati R, Jurklies B, Farkas A, Andreasson S, Weleber RG, Jacobson SG, Rudolph G, Castellan C, Dollfus H, Legius E, Anastasi M, Bitoun P, Lev D, Sieving PA, Munier FL, Zrenner E, Sharpe LT, Cremers FP, Wissinger B. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet. 2005;13:302–8. [PubMed: 15657609]
  • Kohl S, Zobor D, Chiang WC, Weisschuh N, Staller J, Menendez IG, Chang S, Beck SC, Garrido MG, Sothilingam V, Seeliger MW, Stanzial F, Benedicenti F, Inzana F, Héon E, Vincent A, Beis J, Strom TM, Rudolph G, Roosing S, Hollander AI, Cremers FP, Lopez I, Ren H, Moore AT, Webster AR, Michaelides M, Koenekoop RK, Zrenner E, Kaufman RJ, Tsang SH, Wissinger B, Lin JH. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet. 2015;47:757–65. [PMC free article: PMC4610820] [PubMed: 26029869]
  • Komáromy AM, Alexander JJ, Rowlan JS, Garcia MM, Chiodo VA, Kaya A, Tanaka JC, Acland GM, Hauswirth WW, Aguirre GD. Gene therapy rescues cone function in congenital achromatopsia. Hum Mol Genet. 2010;19:2581–93. [PMC free article: PMC2883338] [PubMed: 20378608]
  • Lamb TD, Pugh EN Jr. Phototransduction, dark adaptation, and rhodopsin regeneration the proctor lecture. Invest Ophthalmol Vis Sci. 2006;47:5137–52. [PubMed: 17122096]
  • Langlo CS, Patterson EJ, Higgins BP, Summerfelt P, Razeen MM, Erker LR, Parker M, Collison FT, Fishman GA, Kay CN, Zhang J, Weleber RG, Yang P, Wilson DJ, Pennesi ME, Lam BL, Chiang J, Chulay JD, Dubra A, Hauswirth WW, Carroll J., ACHM-001 Study Group. Residual foveal cone structure in CNGB3-associated achromatopsia. Invest Ophthalmol Vis Sci. 2016;57:3984–95. [PMC free article: PMC4978151] [PubMed: 27479814]
  • Lee H, Purohit R, Sheth V, McLean RJ, Kohl S, Leroy BP, Sundaram V, Michaelides M, Proudlock FA, Gottlob I. Retinal development in infants and young children with achromatopsia. Ophthalmology. 2015;122:2145–7. [PMC free article: PMC4582068] [PubMed: 25972256]
  • Liang X, Dong F, Li H, Li H, Yang L, Sui R. Novel CNGA3 mutations in Chinese patients with achromatopsia. Br J Ophthalmol. 2015;99:571–6. [PubMed: 25637600]
  • Liu C, Varnum MD. Functional consequences of progressive cone dystrophy-associated mutations in the human cone photoreceptor cyclic nucleotide-gated channel CNGA3 subunit. Am J Physiol Cell Physiol. 2005;289:C187–98. [PubMed: 15743887]
  • Mayer AK, Van Cauwenbergh C, Rother C, Baumann B, Reuter P, De Baere E, Wissinger B, Kohl S., ACHM Study Group. CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients. Hum Mutat. 2017;38:1579–91. [PubMed: 28795510]
  • Michaelides M, Aligianis IA, Ainsworth JR, Good P, Mollon JD, Maher ER, Moore AT, Hunt DM. Progressive cone dystrophy associated with mutation in CNGB3. Invest Ophthalmol Vis Sci. 2004;45:1975–82. [PubMed: 15161866]
  • Michaelides M, Aligianis IA, Holder GE, Simunovic M, Mollon JD, Maher ER, Hunt DM, Moore AT. Cone dystrophy phenotype associated with a frameshift mutation (M280fsX291) in the alpha-subunit of cone specific transducin (GNAT2). Br J Ophthalmol. 2003;87:1317–20. [PMC free article: PMC1771876] [PubMed: 14609822]
  • Michalakis S, Geiger H, Haverkamp S, Hofmann F, Gerstner A, Biel M. Impaired opsin targeting and cone photoreceptor migration in the retina of mice lacking the cyclic nucleotide-gated channel CNGA3. Invest Ophthalmol Vis Sci. 2005;46:1516–24. [PubMed: 15790924]
  • Michalakis S, Mühlfriedel R, Tanimoto N, Krishnamoorthy V, Koch S, Fischer MD, Becirovic E, Bai L, Huber G, Beck SC, Fahl E, Büning H, Schmidt J, Zong X, Gollisch T, Biel M, Seeliger MW. Gene therapy restores missing cone-mediated vision in the CNGA3-/- mouse model of achromatopsia. Adv Exp Med Biol. 2012;723:183–9. [PubMed: 22183332]
  • Nasser F, Weisschuh N, Maffei P, Milan G, Heller C, Zrenner E, Kohl S, Kuehlewein L. Ophthalmic features of cone-rod dystrophy caused by pathogenic variants in the ALMS1 gene. Acta Ophthalmol. 2017. Epub ahead of print. [PubMed: 29193673]
  • Nishiguchi KM, Sandberg MA, Gorji N, Berson EL, Dryja TP. Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. Hum Mutat. 2005;25:248–58. [PubMed: 15712225]
  • Okada A, Ueyama H, Toyoda F, Oda S, Ding WG, Tanabe S, Yamade S, Matsuura H, Ohkubo I, Kani K. Functional role of hCngb3 in regulation of human cone cng channel: effect of rod monochromacy-associated mutations in hCNGB3 on channel function. Invest Ophthalmol Vis Sci. 2004;45:2324–32. [PubMed: 15223812]
  • Ouechtati F, Merdassi A, Bouyacoub Y, Largueche L, Derouiche K, Ouragini H, Nouira S, Tiab L, Baklouti K, Rebai A, Schorderet DF, Munier FL, Zografos L, Abdelhak S, El Matri L. Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene. J Hum Genet. 2011;56:22–8. [PubMed: 21107338]
  • Patel KA, Bartoli KM, Fandino RA, Ngatchou AN, Woch G, Carey J, Tanaka JC. Transmembrane S1 mutations in CNGA3 from achromatopsia 2 patients cause loss of function and impaired cellular trafficking of the cone CNG channel. Invest Ophthalmol Vis Sci. 2005;46:2282–90. [PubMed: 15980212]
  • Pedurupillay CR, Landsend EC, Vigeland MD, Ansar M, Frengen E, Misceo D, Strømme P. Segregation of incomplete achromatopsia and alopecia due to PDE6H and LPAR6 variants in a consanguineous family from Pakistan. Genes (Basel). 2016;7:E41. pii. [PMC free article: PMC4999829] [PubMed: 27472364]
  • Peng C, Rich ED, Varnum MD. Achromatopsia-associated mutation in the human cone photoreceptor cyclic nucleotide-gated channel CNGB3 subunit alters the ligand sensitivity and pore properties of heteromeric channels. J Biol Chem. 2003;278:34533–40. [PubMed: 12815043]
  • Piña AL, Baumert U, Loyer M, Koenekoop RK. A three base pair deletion encoding the amino acid (lysine-270) in the alpha-cone transducin gene. Mol Vis. 2004;10:265–71. [PubMed: 15094710]
  • Piriev NI, Viczian AS, Ye J, Kerner B, Korenberg JR, Farber DB. Gene structure and amino acid sequence of the human cone photoreceptor cGMP-phosphodiesterase alpha' subunit (PDEA2) and its chromosomal localization to 10q24. Genomics. 1995;28:429–35. [PubMed: 7490077]
  • Reicher S, Seroussi E, Gootwine E. A mutation in gene CNGA3 is associated with day blindness in sheep. Genomics. 2010;95:101–4. [PubMed: 19874885]
  • Reuter P, Koeppen K, Ladewig T, Kohl S, Baumann B, Wissinger B., Achromatopsia Clinical Study Group. Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia. Hum Mutat. 2008;29:1228–36. [PubMed: 18521937]
  • Rojas CV, Maria LS, Santos JL, Cortes F, Alliende MA. A frameshift insertion in the cone cyclic nucleotide gated cation channel causes complete achromatopsia in a consanguineous family from a rural isolate. Eur J Hum Genet. 2002;10:638–42. [PubMed: 12357335]
  • Rosenberg T, Baumann B, Kohl S, Zrenner E, Jorgensen AL, Wissinger B. Variant phenotypes of incomplete achromatopsia in two cousins with GNAT2 gene mutations. Invest Ophthalmol Vis Sci. 2004;45:4256–62. [PubMed: 15557429]
  • Sharpe LT, Stockman A, Jagle H, Nathans J. Opsin genes, cone photopigments, color vision, and color blindness. In: Gegenfurtner K, Sharpe LT, eds. Color Vision: from Genes to Perception. Cambridge, UK: Cambridge University Press; 1999:3-52.
  • Shimizu-Matsumoto A, Itoh K, Inazawa J, Nishida K, Matsumoto Y, Kinoshita S, Matsubara K, Okubo K. Isolation and chromosomal localization of the human cone cGMP phosphodiesterase gamma cDNA (PDE6H). Genomics. 1996;32:121–4. [PubMed: 8786098]
  • Sidjanin DJ, Lowe JK, McElwee JL, Milne BS, Phippen TM, Sargan DR, Aguirre GD, Acland GM, Ostrander EA. Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum Mol Genet. 2002;11:1823–33. [PubMed: 12140185]
  • Skorczyk-Werner A, Chiang WC, Wawrocka A, Wicher K, Jarmuż-Szymczak M, Kostrzewska-Poczekaj M, Jamsheer A, Płoski R, Rydzanicz M, Pojda-Wilczek D, Weisschuh N, Wissinger B, Kohl S, Lin JH, Krawczyński MR. Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene. Eur J Hum Genet. 2017;25:1210–6. [PMC free article: PMC5643965] [PubMed: 28812650]
  • Sundaram V, Wilde C, Aboshiha J, Cowing J, Han C, Langlo CS, Chana R, Davidson AE, Sergouniotis PI, Bainbridge JW, Ali RR, Dubra A, Rubin G, Webster AR, Moore AT, Nardini M, Carroll J, Michaelides M. Retinal structure and function in achromatopsia: implications for gene therapy. Ophthalmology. 2014;121:234–45. [PMC free article: PMC3895408] [PubMed: 24148654]
  • Sundin OH, Yang JM, Li Y, Zhu D, Hurd JN, Mitchell TN, Silva ED, Maumenee IH. Genetic basis of total colourblindness among the Pingelapese islanders. Nat Genet. 2000;25:289–93. [PubMed: 10888875]
  • Taylor RL, Parry NRA, Barton SJ, Campbell C, Delaney CM, Ellingford JM, Hall G, Hardcastle C, Morarji J, Nichol EJ, Williams LC, Douzgou S, Clayton-Smith J, Ramsden SC, Sharma V, Biswas S, Lloyd IC, Ashworth JL, Black GC, Sergouniotis PI. Panel-based clinical genetic testing in 85 children with inherited retinal disease. Ophthalmology. 2017;124:985–91. [PubMed: 28341476]
  • Thiadens AA, den Hollander AI, Roosing S, Nabuurs SB, Zekveld-Vroon RC, Collin RW, De Baere E, Koenekoop RK, van Schooneveld MJ, Strom TM, van Lith-Verhoeven JJ, Lotery AJ, van Moll-Ramirez N, Leroy BP, van den Born LI, Hoyng CB, Cremers FP, Klaver CC. Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders. Am J Hum Genet. 2009a;85:240–7. [PMC free article: PMC2725240] [PubMed: 19615668]
  • Thiadens AA, Roosing S, Collin RW, van Moll-Ramirez N, van Lith-Verhoeven JJ, van Schooneveld MJ, den Hollander AI, van den Born LI, Hoyng CB, Cremers FP, Klaver CC. Comprehensive analysis of the achromatopsia genes CNGA3 and CNGB3 in progressive cone dystrophy. Ophthalmology. 2010;117:825–30.e1. [PubMed: 20079539]
  • Thiadens AA, Slingerland NW, Roosing S, van Schooneveld MJ, van Lith-Verhoeven JJ, van Moll-Ramirez N, van den Born LI, Hoyng CB, Cremers FP, Klaver CC. Genetic etiology and clinical consequences of complete and incomplete achromatopsia. Ophthalmology. 2009b;116:1984–9.e1. [PubMed: 19592100]
  • Thomas MG, Kumar A, Kohl S, Proudlock FA, Gottlob I. High-resolution in vivo imaging in achromatopsia. Ophthalmology. 2011;118:882–7. [PubMed: 21211844]
  • Thomas MG, McLean RJ, Kohl S, Sheth V, Gottlob I. Early signs of longitudinal progressive cone photoreceptor degeneration in achromatopsia. Br J Ophthalmol. 2012;96:1232–6. [PubMed: 22790432]
  • Tränkner D, Jägle H, Kohl S, Apfelstedt-Sylla E, Sharpe LT, Kaupp UB, Zrenner E, Seifert R, Wissinger B. Molecular basis of an inherited form of incomplete achromatopsia. J Neurosci. 2004;24:138–47. [PubMed: 14715947]
  • Ueno S, Nakanishi A, Kominami T, Ito Y, Hayashi T, Yoshitake K, Kawamura Y, Tsunoda K, Iwata T, Terasaki H. In vivo imaging of a cone mosaic in a patient with achromatopsia associated with a GNAT2 variant. Jpn J Ophthalmol. 2017;61:92–8. [PubMed: 27718025]
  • Varsányi B, Wissinger B, Kohl S, Koeppen K, Farkas A. Clinical and genetic features of Hungarian achromatopsia patients. Mol Vis. 2005;11:996–1001. [PubMed: 16319819]
  • Vincent A, Wright T, Billingsley G, Westall C, Héon E. Oligocone trichromacy is part of the spectrum of CNGA3-related cone system disorders. Ophthalmic Genet. 2011;32:107–13. [PubMed: 21268679]
  • Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334:1081–6. [PubMed: 22116877]
  • Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol. 2012;197:857–67. [PMC free article: PMC3384412] [PubMed: 22733998]
  • Weisschuh N, Mayer AK, Strom TM, Kohl S, Glöckle N, Schubach M, Andreasson S, Bernd A, Birch DG, Hamel CP, Heckenlively JR, Jacobson SG, Kamme C, Kellner U, Kunstmann E, Maffei P, Reiff CM, Rohrschneider K, Rosenberg T, Rudolph G, Vámos R, Varsányi B, Weleber RG, Wissinger B. Mutation detection in patients with retinal dystrophies using targeted next generation sequencing. PLoS One. 2016;11:e0145951. [PMC free article: PMC4713063] [PubMed: 26766544]
  • Weisschuh N, Stingl K, Audo I, Biskup S, Bocquet B, Branham K, Burstedt MS, De Baere E, De Vries MJ, Golovleva I, Green A, Heckenlively J, Leroy BP, Meunier I, Traboulsi E, Wissinger B, Kohl S. Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia. Hum Mutat. 2018. Epub ahead of print. [PubMed: 30080950]
  • Wissinger B, Gamer D, Jagle H, Giorda R, Marx T, Mayer S, Tippmann S, Broghammer M, Jurklies B, Rosenberg T, Jacobson SG, Sener EC, Tatlipinar S, Hoyng CB, Castellan C, Bitoun P, Andreasson S, Rudolph G, Kellner U, Lorenz B, Wolff G, Verellen-Dumoulin C, Schwartz M, Cremers FP, Apfelstedt-Sylla E, Zrenner E, Salati R, Sharpe LT, Kohl S. CNGA3 mutations in hereditary cone photoreceptor disorders. Am J Hum Genet. 2001;69:722–37. [PMC free article: PMC1226059] [PubMed: 11536077]
  • Wiszniewski W, Lewis RA, Lupski JR. Achromatopsia: the CNGB3 p.T383fsX mutation results from a founder effect and is responsible for the visual phenotype in the original report of uniparental disomy 14. Hum Genet. 2007;121:433–9. [PubMed: 17265047]
  • Xu M, Gelowani V, Eblimit A, Wang F, Young MP, Sawyer BL, Zhao L, Jenkins G, Creel DJ, Wang K, Ge Z, Wang H, Li Y, Hartnett ME, Chen R. ATF6 Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement. Invest Ophthalmol Vis Sci. 2015;56:3889–95. [PMC free article: PMC4468593] [PubMed: 26070061]
  • Zein WM, Jeffrey BG, Wiley HE, Turriff AE, Tumminia SJ, Tao W, Bush RA, Marangoni D, Wen R, Wei LL, Sieving PA. CNGB3-achromatopsia clinical trial with CNTF: diminished rod pathway responses with no evidence of improvement in cone function. Invest Ophthalmol Vis Sci. 2014;55:6301–8. [PMC free article: PMC4191169] [PubMed: 25205868]
  • Zelinger L, Cideciyan AV, Kohl S, Schwartz SB, Rosenmann A, Eli D, Sumaroka A, Roman AJ, Luo X, Brown C, Rosin B, Blumenfeld A, Wissinger B, Jacobson SG, Banin E, Sharon D. Genetics and disease expression in the CNGA3 form of achromatopsia: steps on the path to gene therapy. Ophthalmology. 2015;122:997–1007. [PubMed: 25616768]
  • Zobor D, Werner A, Stanzial F, Benedicenti F, Rudolph G, Kellner U, Hamel C, Andréasson S, Zobor G, Strasser T, Wissinger B, Kohl S, Zrenner E. RD-CURE Consortium (2017) The clinical phenotype of CNGA3-related achromatopsia: pretreatment characterization in preparation of a gene replacement therapy trial. Invest Ophthalmol Vis Sci. 2017;58:821–32. [PubMed: 28159970]

Chapter Notes

Author History

Herbert Jägle, MD, FEBO, Dhabil Prof (2004-present)
Susanne Kohl, Bsc, MSc, PhD (2004-present)
Lindsay T Sharpe, BA (Hons), MA, PhD, Dhabil (med); Institute of Ophthalmology, UK (2004-2013)
Ditta Zobor, MD, PhD, FEBO, Dhabil (2018-present)
Bernd Wissinger, BSc, MSc, PhD, Prof (2004-present)

Revision History

  • 20 September 2018 (bp) Comprehensive update posted live
  • 25 February 2016 (sk) Revision: Therapies Under Investigation
  • 29 October 2015 (me) Comprehensive update posted live
  • 27 June 2013 (me) Comprehensive update posted live
  • 23 December 2010 (cd) Revision: sequence analysis available clinically for mutations in GNAT2
  • 23 September 2010 (cd) Revision: prenatal testing available for achromatopsia 2 and 3; achromatopsia 5 (caused by mutations in PDE6C) added; clinical testing and prenatal testing available for PDE6C mutations.
  • 25 June 2009 (me) Comprehensive update posted live
  • 23 October 2006 (me) Comprehensive update posted live
  • 24 June 2004 (me) Review posted live
  • 17 February 2004 (sk, bw) Original submission
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