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Achromatopsia

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

Author Information
, BSc, MSc, PhD
Molecular Genetics Laboratory
Institute for Ophthalmic Research
University of Tübingen
Tübingen, Germany
, MD, FEBO, Dhabil, Prof
Department of Ophthalmology
University of Regensburg
Regensburg, Germany
, BSc, MSc, PhD, Prof
Molecular Genetics Laboratory
Institute for Ophthalmic Research
University of Tübingen
Tübingen, Germany

Initial Posting: ; Last Revision: February 25, 2016.

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 symptoms 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 ERG. Identification of biallelic pathogenic variants in CNGB3, CNGA3, GNAT2, PDE6C, ATF6, or PDE6H confirms the clinical diagnosis and allows for family studies.

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 and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in the family.

GeneReview Scope

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

For synonyms and outdated names see Nomenclature.

Diagnosis

Suggestive Findings

Achromatopsia should be suspected in individuals with following typical clinical findings:

  • Increased sensitivity to light
  • Pendular nystagmus
  • Reduced visual acuity
  • Reduced or complete loss of color discrimination
  • Small central scotoma
  • Eccentric fixation

The following also contribute to the diagnosis:

  • 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.
  • Electrophysiology
    • In the single-flash electroretinogram (ERG), the photopic response (including the 30-Hz flicker response) is absent or markedly diminished while the scotopic response is normal or mildly abnormal.
    • In the 15-Hz flicker ERG a typical finding is the absence of the cone-driven fast pathway response elicited by high flash intensities [Bijveld et al 2011].
  • Fundus appearance. Many affected individuals have a normal-appearing fundus. Others 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.
  • 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, already at early ages [Genead et al 2011, Thomas et al 2011, Sundaram et al 2014, Lee et al 2015].
  • Fundus autofluorescence imaging shows missing or a variable formation of the foveal hypofluorescence or a larger lesion with a surrounding hyperautofluorescent ring and a central region of absent autofluorescence corresponding to the lesion area in the OCT [Greenberg et al 2014, Kohl et al 2015].
  • Visual fields. Small central scotomas can be demonstrated in some individuals by careful testing. However, unsteady fixation can make demonstration of a central scotoma difficult.
  • Family history is consistent with autosomal recessive inheritance.
  • Psychophysical tests, available in specialized centers but not necessary for diagnosis, include the following:
    • Absence of the Kohlrausch kink (cone-rod break) in the dark-adaptation curve in complete achromatopsia
    • Peaking of photopic luminosity or brightness measured as a function of spectral wavelength, whether by flicker photometry, incremental thresholds, or by side-by-side matching, at 507 nm (the peak wavelength of the rod or scotopic visual system) instead of at 555 nm (the peak wavelength of the cone or photopic visual system)

Establishing the Diagnosis

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 (OCT), fundus autofluorescence, visual fields, and ERG. Identification of biallelic pathogenic variants in CNGB3, CNGA3, GNAT2, PDE6C, ATF6 or PDE6H confirms the clinical diagnosis and allows for family studies.

Molecular genetic testing approaches can include serial single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

  • Serial single-gene testing can be considered as biallelic pathogenic variants of CNGB3 account for a large proportion of the achromatopsia (see Table 1). Targeted analysis for the most common pathogenic variant c.1148delC in CNGB3 can be performed first (see Table 1, footnote 6). The following order for serial single-gene testing is provided by the authors to maximize the value of molecular genetic testing. Recommendations are based on the frequency of pathogenic variants in each gene and the predicted cost of sequencing due to gene size [Author, personal observation]:
    1.

    Targeted analysis for c.1148delC in CNGB3

    2.

    Sequence analysis of CNGA3

    3.

    Sequence analysis of CNGB3

    4.

    Sequence analysis of GNAT2

    5.

    Sequence analysis of PDE6C

    6.

    Sequence analysis of ATF6

    7.

    Sequence analysis of PDE6H

  • A multi-gene panel that includes CNGB3, CNGA3, GNAT2, PDE6C, ATF6, PDE6H and other genes of interest (see Differential Diagnosis) may also be considered.
    Note: The genes included and the sensitivity of multi-gene panels vary by laboratory and over time.
  • More comprehensive genomic testing – when available – including whole-exome sequencing (WES) and whole-genome sequencing (WGS) may be considered if serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of achromatopsia. For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetic Testing Used in Achromatopsia

Gene 1Proportion of Achromatopsia Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detected by Test Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
CNGB347%-87% in European
72% in Israeli and Palestinian 5
~100% 6None reported 7
CNGA35%-23% in European
28% in Israeli and Palestinian
80% in Chinese 8
~100%None reported 7
GNAT29 families 9~100%1 family 10
PDE6C13 families 11~100%None reported 7
ATF612 families 12~100%None reported 7
PDE6H2 families 13~100%None reported 7
Unknown10%-25% 14NA
1.
2.

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

3.

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.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can 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.

5.
6.

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 [Kohl et al 2005].

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.
13.

Families from Belgium and the Netherlands [Kohl et al 2012]

14.

Test characteristics. See Clinical Utility Gene Card [Kohl & Hamel 2013] for information on test characteristics including sensitivity and specificity.

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 loss 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.

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

Genotype-Phenotype Correlations

In the majority of individuals affected by autosomal recessive achromatopsia, pathogenic variants in CNGB3, CNGA3, GNAT2, PDE6C, and ATF6 result in the complete form of the disorder. Certain pathogenic variants in GNAT2 and CNGA3 are associated with a very mild phenotype of incomplete achromatopsia and oligo-cone trichromacy [Rosenberg et al 2004, Vincent et al 2011]. Pathogenic variants in PDE6H lead to the incomplete form of achromatopsia [Kohl et al 2012]. Cone-rod degeneration has been described but the differentiation from achromatopsia can be difficult and the diagnosis of cone or cone-rod dystrophy can often only be established by the observation of disease progression. Thus the incidence is as yet unclear.

Nomenclature

The complete form of autosomal recessive achromatopsia is also referred to as rod monochromacy (monochromatism), complete (or total) color blindness (OMIM), 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 autosomal recessive achromatopsia is also known clinically as atypical, incomplete achromatopsia or incomplete achromatopsia with reduced visual acuity.

Prevalence

Autosomal recessive achromatopsia is a rare disorder with an estimated prevalence of less 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: severely reduced visual acuity, pendular nystagmus, increased sensitivity to light, and reduced or complete loss of color discrimination and other psychophysical and electroretinographic findings. The following retinopathies may be confused with achromatopsia.

Blue-cone monochromatism. (OMIM) Like achromatopsia, blue-cone monochromacy (also referred to as S-cone monochromacy or X-chromosome-linked achromatopsia) is characterized by severely reduced visual acuity, eccentric fixation, infantile nystagmus, no obvious fundus abnormalities, and poor or no color discrimination [Sharpe et al 1999]. However, unlike achromatopsia, the peak of the photopic luminosity function is near 440 nm (the peak sensitivity of the S cones), not 507 nm (the peak sensitivity of the rods); and cone electroretinogram responses can be elicited by presenting blue flashes on a yellow background. This is because the S cones are functioning in addition to the rods. 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 (see Red-Green Color Vision Defects). Blue-cone monochromacy affects mostly males and is inherited in an X-linked manner. A special four-color plate test or a two-color filter test can clinically distinguish blue-cone monochromats from achromats (rod monochromats).

Cone dystrophies. In cone dystrophy, cone function is normal at birth. Typical symptoms appear later. These include reduced visual acuity, photophobia, increased sensitivity to glare, and abnormal color vision [Holopigian et al 2004]. The age of onset of vision loss may be as early as childhood or as late as the seventh decade. Differentiating between achromatopsia and cone dystrophy can be difficult, particularly in individuals with onset in early childhood; the best clinical discriminator is disease progression, which occurs in cone dystrophy and typically not in individuals with achromatopsia. However, in achromatopsia and cone dystrophy, dark-adapted rod thresholds may be elevated [Aboshiha et al 2014].

Hereditary red-green color vision defects. Hereditary red-green color vision defects manifest mostly in males; the condition is not accompanied by ophthalmologic or other associated clinical abnormalities. Most individuals with protanomalous and deuteranomalous color vision defects (i.e., anomalous trichromats) have no major problems in naming colors; 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.

Clinical chart tests widely used to detect red-green color vision defects include Ishihara plates and the American Optical HRR pseudoisochromatic plates. Definitive classification of the color vision defects known as protanopia, deuteranopia, protanomaly, and deuteranomaly requires use of the anomaloscope, which involves color matching.

Variants associated with red-green color vision defects either affect OPN1LW (long-wave-sensitive opsin 1), encoding the red pigment, or OPN1MW (medium-wave-sensitive opsin 1), encoding the green pigments. Inheritance is X-linked.

Tritan and yellow-blue defects (OMIM). Often referred to as yellow-blue disorders, although the color confusion is typically between blues and greens, tritan defects affect the S (blue) cones. In individuals with congenital tritan defects, they arise from pathogenic variants in OPN1SW (short-wave-sensitive opsin 1) located on chromosome 7. They often remain undetected because of their rarity, frequent incomplete manifestation, and the limited nature of the color confusion (blues and greens). Other non-congenital yellow-blue deficits, which are similar in some ways to tritan defects, may result from aging or disorders of the choroid, the pigment epithelium, the retina, or the optic nerve (e.g., optic atrophy type 1). They are usually progressive and have other related signs, such as associated visual acuity defects [Sharpe et al 1999].

Cerebral achromatopsia. Cerebral achromatopsia or dyschromatopsia, which is associated with severe or total color vision deficits, can arise adventitiously after brain fever, cortical trauma, or cerebral infarction, especially involving lesions to the ventral occipital cortex [Bouvier & Engel 2006].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with achromatopsia, the following evaluations are recommended:

  • Standard clinical ophthalmologic evaluation and testing
  • Electrophysiologic examination
  • Color vision evaluation
  • Dark adaptometry
  • Consultation with a medical geneticist and/or genetic counselor

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.

Children with achromatopsia should have preferential seating in the front of the class to benefit maximally from their magnifying devices.

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 and 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 (NCT01648452) 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].

Most recently, a clinical Phase I/II safety trial for gene replacement therapy using viral AAV vectors for CNGA3-related achromatopsia has been approved by the German legal authorities (NCT02610582). Similar trials for CNGB3-associated achromatopsia are in preparation, and recruiting individuals for clinical assessment to establish the natural history of this disease (NCT01846052).

Search ClinicalTrials.gov for access to 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 CNGB3, CNGA3, GNAT2, PDE6C, ATF6, or PDE6H 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 a pathogenic variant in CNGB3, CNGA3, GNAT2, PDE6C, ATF6, or PDE6H.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a CNGB3, CNGA3, GNAT2, PDE6C, ATF6, or PDE6H pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the CNGB3, CNGA3, GNAT2, PDE6C, ATF6, or PDE6H 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

If the CNGB3, CNGA3, GNAT2, PDE6C, ATF6, or PDE6H pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of the gene of interest or custom prenatal testing.

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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the CNGB3, CNGA3, GNAT2, PDE6C, ATF6, or PDE6H pathogenic variants have been identified.

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 at the guanosine binding site of the transducin alpha subunit (GNAT2) and its subsequent release from the inhibitory beta/gamma subunits. The activated GTP-transducin then binds and activates the alpha’-subunit of the cone phosphodiesterase (PDE6C) by retracting the inhibitory gamma-subunit (PDE6H). PDE hydrolyzes cGMP and effectively reduces its intracellular concentration. This results in the closure of the hetero-tetrameric cGMP-gated cation channels (CNGA3 and CNGB3) and, subsequently, in membrane hyperpolarization [Lamb & Pugh 2006]. Transducin thus mediates the first step, the phosphodiesterase the intermediate, while the cGMP-gated channel represents the final component of the phototransduction cascade. In contrast, the most recently identified ACHM-related gene, ATF6, encodes for a ubiquitously expressed transmembrane transcription factor, well 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.

Functional analysis by heterologous expression of mutant cyclic nucleotide-gated (CNG) channels has shown that in many cases channel function is strongly impaired or completely absent (see CNGA3 Abnormal gene product, CNGB3 Abnormal gene product).

In addition, animal models have helped to clarify the underlying pathogenic mechanisms. The analysis of the orthologous Cnga3 knockout mouse model shows complete absence of physiologically measurable 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 down-regulate 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. Cone degeneration in the Cnga3 knockout animals is evident from the second postnatal week on and proceeds significantly faster in the ventral than in the dorsal part of the retina. In addition, Cnga3 appears to be essential for normal postnatal migration of cone somata [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].

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].

Two naturally occurring canine models for CNGB3 have been identified. It has been shown that autosomal recessive canine cone degeneration (cd) in the Alaskan malamute and the German shorthaired pointer breeds is caused by pathogenic variants in canine CNGB3, a deletion of the complete gene in the former and a pathogenic missense variant in the latter [Sidjanin et al 2002]. In the Alaskan malamute, cone-degenerate pups develop day-blindness and photophobia. Symptoms are present only in bright light; vision in dim light is normal. Affected dogs remain ophthalmoscopically normal throughout life. Cone function, detectable on electroretinogram in very young cd-affected pups, begins to fail at a few weeks' age and is undetectable in mature cd-affected dogs. Adult cd-affected retinas lack all cones. Cones degenerate by extrusion of the nucleus into the inner segment and later displacement of the cone nuclei in the interphotoreceptor space. 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]

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. Rod-mediated waveforms are normal, but decline with age in homozygous mice but also wild type littermates. Microscopy of the retina reveals progressive vacuolization of the photoreceptor outer segments. Immunocytochemistry with cone-specific markers show progressive loss of labeling for Gnat2 protein, but the cone outer segments in the oldest mice examined remain intact and positive for peanut agglutinin (PNA) [Chang et al 2006].

The cone photoreceptor function loss 1 (cpfl1) mouse mutant is a model for achromatopsia related to pathogenic variants in Pde6c [Chang et al 2009], due to the presence of a 116-bp insertion between exon 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) in the cpfl1 mouse. Both pathogenic variants result in frame-shifts that predict a truncated polypeptide. The phenotype can be easily typed by ERG as early as age three weeks. While dark-adapted ERG responses are normal, light-adapted responses representing cone function are virtually absent. 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. In addition, some swollen and pyknotic nuclei were observed in the inner nuclear layer. Loss of cones further proceeds so that only very few could be detected in retinal sections of five-month-old animals [Chang et al 2009].

In contrast, neither the Pde6h nor the Atf6 knock-out mouse models recapitulate the human achromatopsia phenotype [Brennenstuhl et al 2015, Kohl 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.

Benign allelic variants. Only a few polymorphisms and rare variants are observed; most occur within non-coding regions or do not result in an amino acid substitution.

Pathogenic allelic variants. More than 40 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]. The vast majority are pathogenic nonsense variants, frame-shift 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 and results from a founder effect [Wiszniewski et al 2007].

Table 2.

CNGB3 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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

Abnormal gene product. Most CNGB3-encoded mutant proteins are thought to be null alleles (i.e., produce no appreciable protein product). Coexpression of a presumptive null variant, p.Thr383IlefsTer13 (c.1148delC), the most common pathogenic variant associated with achromatopsia, produced channels with properties indistinguishable from homomeric CNGA3 channels, providing further support for a null allele status [Peng et al 2003, Okada et al 2004, Bright et al 2005].

However, certain disease-associated variants in the subunit encoded by CNGB3 are apparent gain-of-function variants [Okada et al 2004, Bright et al 2005]. Heterologous coexpression of human normal CNGA3 and mutated CNGB3 containing the Pingelapese blindness-associated p.Ser435Phe variant generated functional heteromeric channels. These channels 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.

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.

Benign allelic variants. Only a few benign variants and some rare variants are observed; most occur within non-coding regions or do not result in an amino acid substitution.

Pathogenic allelic variants. More than 80 different pathogenic variants have been reported [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. The polypeptide is 694 amino acids long and has a size 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]. CNGA3 encodes the cyclic nucleotide-gated cation channel alpha 3 (the alpha subunit of the cone photoreceptor cGMP-gated cation channel [CNG]). In vitro expression experiments have shown that alpha subunits on CNG channels alone are able to form functional homo-oligomeric channels, yet their biophysical properties differ from those of heteromeric native CNG channels consisting of two alpha and two beta subunits.

Abnormal gene product. The pathogenic missense variants mostly affect amino acid residues highly conserved among the members of the cyclic nucleotide-gated channel family and cluster at structural and functional domains including the cGMP-binding domain [Wissinger et al 2001]. In vitro expression experiments have shown that most pathogenic variants lead to a complete lack of channel activity. Full-length mutant proteins are synthesized but retained in the endoplasmic reticulum; cellular trafficking is therefore impaired [Faillace et al 2004, Patel et al 2005, Koeppen et al 2008, Reuter et al 2008].

However, some pathogenic variants have been shown to be associated with incomplete achromatopsia (i.e., residual but disturbed cone function). Psychophysical and electroretinographic analyses in these individuals demonstrate that the light sensitivity of the cone system is lowered and the signal transfer from cones to secondary neurons is perturbed [Tränkner et al 2004]. Heterologous expression reveals that CNGA3-encoded polypeptides carrying certain nucleotide variants, especially in the pore region and the cGMP binding domain, 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. Surprisingly, coexpression of some of these mutant channels with wild type CNGB3 subunits rescue the channel function to some extent [Tränkner et al 2004, Liu & Varnum 2005, Reuter et al 2008]. In addition, pathogenic variants in the pore can lead to impaired surface expression or reduced macroscopic currents [Koeppen 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.

Benign allelic variants. Only a few polymorphisms and rare variants are observed; most occur within non-coding regions or do not result in an amino acid substitution.

Pathogenic allelic variants. Only ten 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 frame-shift and PTC) segregating in nine independent families 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].

Table 3.

GNAT2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The polypeptide is 354 amino acids long. 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.

Abnormal gene product. Functional in vitro splicing assays have shown that the c.461+24G>A variant results in leaky aberrant splicing, also giving rise to small amounts of correctly spliced transcripts and resulting in a milder phenotype best described as incomplete achromatopsia or oligo-cone trichromacy [Rosenberg et al 2004]. All other pathogenic variants result in PTC (premature termination codon) and in strongly truncated transducin polypeptides lacking considerable proportions of the genuine carboxy terminus that is thought to interact with the photo pigment [Cai et al 2001].

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.

Benign allelic variants. Several polymorphisms and rare variants are observed; most occur within non-coding regions or do not result in an amino acid substitution.

Pathogenic allelic variants. To date nineteen different pathogenic variants in PDE6C in thirteen independent families have been described, including 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].

Table 4.

PDE6C Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.85C>Tp.Arg29TrpNM_006204​.3
NP_006195​.3

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The PDE6C transcript of 3,307 bp encodes for the phosphodiesterase 6C, cGMP-specific, cone, alpha-prime; PDE6C. This alpha’-subunit of the cone-specific phosphodiesterase consists of 858 amino acid residues.

Abnormal gene product. Functional in vitro assays analyzing the enzymatic activity of PDE6C pathogenic missense variants show markedly reduced to complete loss of enzymatic activity [Chang et al 2009].

ATF6

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

Benign allelic variants. Several polymorphisms and rare variants are observed; most occur within non-coding regions or do not result in an amino acid substitution.

Pathogenic allelic variants. Ten different pathogenic variants have been reported in 12 families [Ansar et al 2015, Kohl et al 2015, Xu et al 2015]. Eight of the ten are nonsense variants, small insertions, and deletions, as well as pathogenic variants at the canonic splice sites. Only two missense pathogenic variants have been observed, one of which (c.970C>T) was functionally characterized, and shown to impair transcriptional activity [Kohl et al 2015]. Homozygous c.970C>T variants were identified in affected individuals from two independent families of Irish/British descent; the families were shown to carry a common haplotype of 0.7 Mb suggestive of a founder variant. Another pathogenic variant, c.1533+1G>C was observed recurrently in four families originating from French Canada, also suggesting that this pathogenic variant represents a founder variant in this population [Kohl et al 2015, Xu et al 2015].

Table 6.

ATF6 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid 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 (www​.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) in the promoter regions of genes encoding ER protein chaperones, ER-associated protein degradation and ER protein trafficking. On induction of ER stress, the cytosolic ~400-residue N-terminal portion of ATF6 (N-ATF6) is released as a result of regulated intramembraneous proteolysis. 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 of the pathogenic missense variants result either in severely truncated polypeptides or – more likely – will be degraded by the mechanism of nonsense-mediated decay. One missense pathogenic variant was functionally characterized: p.Arg324Cys localizes to the basic region of the bZIP domain, affecting an arginine residue that is not only conserved among transcription factors of the ATF family but also in those of the AP-1 family. The impact of this disease-causing variant on the unfolded protein response was tested in patient derived-fibroblasts homozygous for this ATF6 pathogenic variant as well as in in vitro experiments, and shown to result in complete loss of induction of downstream products. Both results indicated that the ATF6 pathogenic variant p.Arg324Cys severely impairs ATF6 transcriptional activity [Kohl et al 2015].

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.

Benign allelic variants. Only few polymorphisms and rare variants are observed.

Pathogenic allelic variants. To date only a single homozygous pathogenic nonsense variant c.35C>G in PDE6H in three affected individuals from two independent families originating from Belgium and the Netherlands have been described [Kohl et al 2012].

Table 5.

PDE6H Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The PDE6H transcript encodes for the phosphodiesterase 6H, cGMP-specific, cone, gamma; PDE6H, the inhibitory gamma-subunit of the cone photoreceptor phosphodiesterase. It is a small protein consisting of only 83 amino acid residues.

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Suggested Reading

  1. Aboshiha J, Dubis AM, Carroll J, Hardcastle AJ, Michaelides M (2015) The cone dysfunction syndromes. Br J Ophthalmol. 2015 Mar 13. pii: bjophthalmol-2014-306505.
  2. Deeb SS. Molecular genetics of colour vision deficiencies. Clin Exp Optom. 2004;87:224–9. [PubMed: 15312026]
  3. Michaelides M, Hunt DM, Moore AT. The cone dysfunction syndromes. Br J Ophthalmol. 2004;88:291–7. [PMC free article: PMC1771989] [PubMed: 14736794]

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 Opthalmology, UK (2004-2013)
Bernd Wissinger, BSc, MSc, PhD, Prof (2004-present)

Revision History

  • 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 to live Web site
  • 24 June 2004 (me) Review posted to live Web site
  • 17 February 2004 (sk, bw) Original submission
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