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Achromatopsia

Synonyms: Rod Monochromatism, Total Color Blindness

, 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 Update: June 27, 2013.

Summary

Disease 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.

Diagnosis/testing. The diagnosis of achromatopsia is based on medical history, color vision testing, electrophysiologic examination, and absent or only minor fundus changes. Mutations in one of five genes (CNGB3, CNGA3, GNAT2, PDE6C, or PDE6HI) are known to cause achromatopsia.

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; occupational aids.

Surveillance: Ophthalmologic examination annually 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 family members and prenatal testing for pregnancies at increased risk are possible once the disease-causing mutations have been identified in the family.

Diagnosis

Clinical Diagnosis

The clinical diagnosis of achromatopsia is based on the presence of typical clinical findings:

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

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 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 in the fovea can occur in older individuals.
  • 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)
  • 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 may be observed [Genead et al 2011, Thomas et al 2011].

Molecular Genetic Testing

Genes. To date, mutations in one of five genes are known to cause autosomal recessive achromatopsia:

Evidence for locus heterogeneity. An additional locus (ACHM1) had been assigned to chromosome 14 as a result of a single case of maternal uniparental isodisomy of chromosome 14. This locus had to be revised as the patient described in the original report was later shown to be homozygous for c.1148delC, the most common mutation in CNGB3 [Wiszniewski et al 2007].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Achromatopsia

Gene 1 Proportion of Achromatopsia Attributed to Mutations in This GeneTest MethodMutations Detected 2
CNGB3~40-50%Targeted mutation analysisc.1148delC 3
Sequence analysis 4Sequence variants
Deletion/duplication analysis 5Unknown
CNGA3~25%Sequence analysis 4Sequence variants
Deletion/duplication analysis 5Unknown
GNAT2<2%Sequence analysis 4Sequence variants 6
Deletion/duplication analysis 5Exonic or whole-gene deletions
PDE6C<2%Sequence analysis 4Sequence variants
PDE6H~0.3%Sequence analysis 4Sequence variants

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Of 163 individuals with mutations in CNGB3, 105 (64%) were homozygotes, 44 (27%) were compound heterozygotes, and in 14 (9%) only one mutation was identified [Kohl et al 2005].

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. Rosenberg et al [2004]

Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at www.eurogentest.org [Kohl & Hamel 2013 (full text)].

Testing Strategy

To confirm/establish the diagnosis in a proband, the order of molecular genetic testing is the following:

1.

Targeted mutation analysis for the most common mutation 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 PDE6H

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

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

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, mutations in CNGA3, CNGB3, GNAT2 and PDE6C result in the complete form of the disorder. Certain mutations 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]. Mutations in PDE6H lead to the incomplete form of achromatopsia [Kohl et al 2012].

Nomenclature

The complete form of autosomal recessive 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 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 mutation 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. 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 ERG 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 loss of and inactivating mutations in the X-linked opsin gene array or by loss of a critical region that regulates the expression of the red/green gene array (locus control region) (see Red-Green Color Vision Defects). A special four-color plate test or a two-color filter test can clinically distinguish blue-cone monochromats from achromats (rod monochromats).

Cone monochromatism (complete achromatopsia with normal visual acuity). Achromatopsia is less often confused with two other extremely rare forms of cone monochromatism, in which nystagmus and light aversion are not present and the visual acuity and the cone ERG are normal:

  • L- or red-cone monochromacy, in which only the L cones may be functioning in addition to the rods
  • M- or green-cone monochromacy, in which only the M cones may be functioning in addition to the rods [Sharpe et al 1999]. In both disorders, color discrimination may be lacking or unreliable.

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 not typically in individuals with achromatopsia. In contrast with achromatopsia, dark-adapted rod thresholds are typically elevated by approximately 0.5 log unit in cone dystrophy.

  • Cone dystrophy with supernormal rod response. This distinctive form of cone dystrophy is characterized by a steep slope in the relationship between the dark-adapted electroretinogram response amplitude and flash intensity, ending with a higher than normal response amplitude [Gouras et al 1983, Alexander & Fishman 1984]. Visual acuity is typically severely reduced from early childhood and the visual field shows a central scotoma. Color vision defects are in particular red-green-defects in the panel test, but Rayleigh-anomaloscope matches may be similar to those of achromats. Dark-adapted rod and cone thresholds are both elevated. The rod and cone dysfunction is caused exclusively by mutations in KCNV2, encoding a modulatory, electrophysiologically silent subunit of a voltage-gated potassium channel [Wu et al 2006, Thiagalingam et al 2007, Ben Salah et al 2008, Wissinger et al 2008].

Hereditary red-green color vision defects are manifest in early infancy, 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 problems in naming colors; some males with mildly defective red-green color vision may not be aware of it until they are tested. Among persons of northern European origin, approximately 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 protanopia, deuteranopia, protanomaly, and deuteranomaly requires use of the anomaloscope, which involves color matching.

The two genes associated with red-green color vision defects are OPN1LW (opsin 1 long wave), encoding the L (red) pigment and OPN1MW (opsin 1 middle wave), encoding the M (green) pigment. Inheritance is X-linked.

Tritan and yellow-blue defects. 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 congenital cases, they arise from mutations in the gene encoding the S-cone opsin, 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 cases of 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. 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].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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
  • Medical genetics consultation

Treatment of Manifestations

Dark or special filter glasses or red-tinted contact lenses reduce photophobia and may improve visual acuity [Park & Sunness 2004].

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 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 started. The primary outcome of this clinical trial has not yet been published.

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 and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with achromatopsia are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

If the disease-causing mutations have been identified in the family, carrier testing for family members at risk is possible either through laboratories offering testing for the gene of interest or custom testing.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the disease-causing mutations 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
610024RETINAL CONE DYSTROPHY 3A; RCD3A
613093CONE DYSTROPHY 4; COD4
613856ACHROMATOPSIA 4; ACHM4

Molecular Genetic Pathogenesis

CNGA3, CNGB3, GNAT2, PDE6C 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/CNGB3) and, subsequently, membrane hyperpolarization [Lamb & Pugh 2006]. Transducin thus mediates the first step, the phosphodiesterase intermediate, while the cGMP-gated channel represents the final component of the phototransduction cascade.

Functional analysis by heterologous expression of mutant 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 may help 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. An apoptotic cell death is induced; however, loss of Cnga3 does not seem 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].

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 mutations in canine CNGB3 [Sidjanin et al 2002]. In the Alaskan malamute, cone-degenerate pups develop dayblindness 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. Genetic analysis has shown that in the Alaskan malamute the disease is caused by deletion of the complete gene, while in the German shorthaired pointers, the disease is caused by a missense mutation.

The mouse model Gnat2(cpfl3) (cpfl3 = cone photoreceptor function loss, 3) for achromatopsia related to GNAT2 mutations carries a homozygous missense mutation c.598G>A (p.Asp200Asn) in exon 6 of murine Gnat2 [Chang et al 2006]. Homozygous cpfl3 mice have poor cone-mediated responses on ERG at three weeks that become undetectable by nine months. Rod-mediated waveforms are normal, but decline with age in Gnat2(cpfl3) mice but also wild type litter mates. 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 mutations in Pde6c [Chang et al 2009], due to the presence of a 116-bp insertion between exon 4 and 5 (c.864_865ins116) and an additional 1-bp deletion in exon 7 (c.1042delT) in cis (on the same allele) in the cpfl1 mouse. The mutations result in a frame-shift introducing a premature termination codon (p.Glu289fsTer297). The phenotype can be easily typed by electroretinography (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].

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 Symbol.

Benign allelic variants. Only a few benignic 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 mutations have been reported [Kohl et al 1998, Wissinger et al 2001, Johnson et al 2004, Trankner et al 2004, Nishiguchi et al 2005, Varsanyi 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 mutations are missense (<80%). Only a few nonsense mutations, 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 missense mutations 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 mutations 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 mutations 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 [Trankner et al 2004]. Heterologous expression reveals that CNGA3-encoded polypeptides carrying certain point mutations, 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 [Trankner et al 2004, Liu & Varnum 2005, Reuter et al 2008]. In addition, mutations in the pore can lead to impaired surface expression or reduced macroscopic currents [Koeppen et al 2010].

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 Symbol.

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 mutations 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, Varsanyi et al 2005, Khan et al 2007, Wiszniewski et al 2007, Thiadens et al 2009b, Azam et al 2010]. The vast majority are nonsense mutations, frame-shift deletions and insertions, and putative splice site mutations. Only a few missense mutations (~10%) have been observed. One, resulting in the p.Ser435Phe mutant 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 mutation 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 Change Protein 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 mutation, p.Thr383IlefsTer13 (c.1148delC), the most common mutation 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 mutations in the subunit encoded by CNGB3 are apparent gain-of-function mutations [Okada et al 2004, Bright et al 2005]. Heterologous coexpression of human normal CNGA3 and mutated CNGB3 containing the Pingelapese blindness-associated mutation p.Ser435Phe 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.

GNAT2

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

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 mutations (one nonsense mutation, seven deletions and/or insertions, one large deletion of exon 4, and a mutation c.461+24G>A activating a cryptic splice site and resulting in frame-shift and PTC) segregating in eight 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].

Table 3. GNAT2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change Protein 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 mutation is a so-called leaky splicing mutation 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 mutations result in PTC (premature termination codon) and in strongly truncated transducin polypeptides lacking considerable proportions of the genuine carboxyterminus 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 Symbol.

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 sixteen different mutations in PDE6C in eight independent families have been described: seven missense and two nonsense mutations, three small indels, and four mutations affecting splicing [Chang et al 2009, Thiadens et al 2009b, Grau et al 2011].

Table 4. PDE6C Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change Protein 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 missense mutations show markedly reduced to complete loss of enzymatic activity [Chang et al 2009].

PDE6H

Gene structure. PDE6C consists of only three coding exons [Shimizu-Matsumoto et al 1996]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

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

Pathogenic allelic variants. To date only a single homozygous nonsense mutation 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 Change Protein 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.

References

Literature Cited

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Suggested Reading

  1. Deeb SS. Molecular genetics of colour vision deficiencies. Clin Exp Optom. 2004;87:224–9. [PubMed: 15312026]
  2. 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

  • 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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