Alternative titles; symbols
ORPHA: 49382; DO: 0110007;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q11.2 | Achromatopsia 2 | 216900 | Autosomal recessive | 3 | CNGA3 | 600053 |
A number sign (#) is used with this entry because of evidence that complete achromatopsia and some cases of incomplete achromatopsia are caused by homozygous or compound heterozygous mutation in the CNGA3 gene (600053), which encodes the alpha subunit of the cone photoreceptor cGMP-gated cation channel, on chromosome 2q11.
Total colorblindness, also referred to as rod monochromacy or complete achromatopsia, is a rare congenital autosomal recessive disorder characterized by photophobia, reduced visual acuity, nystagmus, and the complete inability to discriminate between colors. Electroretinographic recordings show that in achromatopsia the rod photoreceptor function is normal, whereas cone photoreceptor responses are absent (summary by Kohl et al., 1998).
Genetic Heterogeneity of Total Achromatopsia
A form of achromatopsia previously designated achromatopsia-1 (ACHM1) was later found to be the same as achromatopsia-3 (ACHM3; 262300), caused by mutation in the CNGB3 gene (605080). ACHM4 (613856) is caused by mutation in the GNAT2 gene (139340); ACHM5 (613093) is caused by mutation in the PDE6C gene (600827); ACHM6 (see 610024) is caused by mutation in the PDE6H gene (601190); and ACHM7 (616517) is caused by mutation in the ATF6 gene (605537).
Patients with achromatopsia have poor visual acuity, photophobia, congenital nystagmus, and colorblindness. Photophobia is striking, even in light of ordinary intensity. Vision in ordinary light is severely restricted, and relatively better in dim light. The fundus appears normal (summary by Zlotogora, 1995).
The largest pedigree reported with achromatopsia is that of a family residing on the Island of Fuur in the Limfjord in the north of Denmark (Holm and Lodberg, 1940; Franceschetti et al., 1963).
Mantyjarvi (1978) described affected brothers and a sister with first-cousin parents. Sloan (1954) observed second-cousin parents in 2 instances. Voke-Fletcher (1978) described affected brother and sister with first-cousin parents. Both sibs had marked lateral nystagmus and photophobia.
Typical rod monochromats have normal levels of rhodopsin and normal rod function but lack all sensitivity mediated by cone pigments. Some atypical rod monochromats behave as if they have only rod vision; however, reflection densitometry shows that their retinas contain normal quantities of cone pigments (Alpern, 1974), suggesting that the defect is located distal to the point of light absorption. Presumably the site of the mutation in this disorder is different from that in total colorblindness.
Simunovic et al. (2001) examined red-green color-deficient subjects, a small sample of monochromats, and age-matched color-normal control subjects to determine whether color vision deficiency confers a selective advantage under scotopic conditions. They found no evidence that red-green color deficiency or monochromatism confers a selective advantage under scotopic conditions, including dark adaptation, scotopic visual field sensitivity, or performance on a scotopic perceptual task.
Using optical coherence tomography, Varsanyi et al. (2007) examined in vivo the anatomic structure of the retina in patients with achromatopsia and controls. In patients with achromatopsia, statistically significant reductions were found in total macular volume and in the thickness of the central retina compared with controls. Varsanyi et al. (2007) stated that a possible reason for the structural alteration is the qualitative and/or quantitative disorder of the cone photoreceptors, as the morphologic change is most expressed in the foveola.
Liang et al. (2015) reported 15 Chinese patients with achromatopsia from 10 unrelated families. All patients had poor visual acuity since birth, congenital nystagmus, photophobia, color vision disturbances, and absent or residual cone responses with normal rod responses on electroretinography. Best corrected visual acuity ranged from 20/100 to 10/400. Spectral-domain optical coherence tomography (SD-OCT) revealed disruption or loss of the macular inner-outer segment junction of the photoreceptors.
Zelinger et al. (2015) found that most of the Israeli and Palestinian patients from 41 families with ACHM2 in their cohort showed severely reduced visual acuity, photoaversion, nystagmus, nondetectable cone ERG responses, and impaired color discrimination. Visual acuity usually ranged from finger counting to 0.2 and refractive errors ranged from high myopia to high hypermetropia, with hypermetropia being most common.
Zlotogora (1995) stated that this usually very rare disorder is relatively frequent among Moroccan, Iraqi, and Iranian Jews.
Zelinger et al. (2015) found that the prevalence of ACHM was 1:5,000 among Arab Muslims residing in Jerusalem. The most common mutations in this population were 2 founder mutations in the CNGA3 gene (c.1585G-A, 600053.0008 and c.940_942delATC).
Achromatopsia-2 is an autosomal recessive disorder (Kohl et al., 1998).
Park and Sunness (2004) reported that red contact lenses successfully alleviated photophobia in patients with cone disorders.
Arbour et al. (1997) performed a genomewide search for linkage with total colorblindness using an inbred Jewish kindred from Iran. They used a DNA-pooling strategy that took advantage of the likelihood that the disease in this inbred kindred was inherited by all affected individuals from a common founder. Equal molar amounts of DNA from all affected individuals were pooled and used as a PCR template for short tandem repeat polymorphic markers (STRPs). Pooled DNA from unaffected members of the kindred was used as a control. A reduction in the number of alleles in the affected versus control pools was observed at several loci. Upon genotyping of individual family members, significant linkage was established between the disease phenotype and markers localized on chromosome 2. The highest lod score observed was 5.4 (theta = 0.0). When 4 additional small unrelated families were genotyped, the combined peak lod score was 8.2. Analysis of recombinant chromosomes revealed that the disease gene lies within a 30-cM interval that spans the centromere. Additional fine-mapping studies identified a region of homozygosity in all affected individuals, narrowing the region to 14 cM. Linkage analysis in this kindred initially involved an examination of markers on chromosome 14 because Pentao et al. (1992) had found maternal isodisomy of chromosome 14 in a patient with rod monochromacy. No linkage with chromosome 14 markers was found in the Iranian Jewish kindred. The chromosomal assignment for the achromatopsia locus was given as 2p11.2-q12.
Wissinger et al. (1998) refined the map location for rod monochromacy to an approximately 3-cM interval between markers D2S2175 and D2S373 on 2q11 and showed that this interval includes the gene encoding the alpha-subunit of the cGMP-gated cation channel in cone photoreceptors (CNGA3; 600053).
The British expression 'day blindness' is a good one because the cones are defective and the subjects see better at night. This term is parallel to night blindness (McKusick, 1992).
Kohl et al. (1998) identified missense mutations (600053.0001-600053.0005) in CNGA3 in 5 families with rod monochromacy. In 2 families the mutations were homozygous, whereas the remaining families showed compound heterozygous mutations. In all cases, the segregation pattern was consistent with autosomal recessive inheritance of the disease. This was the first report of a color vision disorder caused by defects other than mutations in the cone pigment genes, and implied, at least in this instance, a common genetic basis for phototransduction in the 3 different cone photoreceptors of the human retina.
Wissinger et al. (2001) screened for CNGA3 mutations in 258 independent families with hereditary cone photoreceptor disorders and found CNGA3 mutations not only in patients with the complete form of achromatopsia, but also in patients with incomplete achromatopsia and even in a few patients diagnosed with severe progressive cone dystrophy. Mutations were identified in 53 families and included 8 previously described mutations and 38 novel mutations. These mutations comprised 39 amino acid substitutions, 4 stop-codon mutations, two 1-bp insertions, and one 3-bp in-frame deletion. Most of the amino acid substitutions affected residues conserved in the CNG channel family and were clustered at the cytoplasmic face of transmembrane domains (TM) S1 and S2, in TM S4, and in the cGMP-binding domain. Four mutations, arg277 to cys (R277C; 600053.0009), arg283 to trp (R283W; 600053.0002), arg436 to trp (R435W; 600053.0010), and phe547 to leu (F547L; 600053.0006), accounted for 41.8% of all the detected mutations.
Wiszniewski et al. (2007) analyzed the CNGA3, CNGB3, and GNAT2 (139340) genes in 16 unrelated patients with autosomal recessive ACHM: 10 patients had mutations in CNGB3, 3 had mutations in CNGA3, and no coding region mutations were found in 3 patients. The authors concluded that CNGA3 and CNGB3 mutations are responsible for the substantial majority of achromatopsia.
Zelinger et al. (2010) identified a mutation in the CNGA3 gene (V529M; 600053.0008) in Arab Muslim and Oriental Jewish families with achromatopsia; the mutation was also identified in 3 previously unreported Christian European families. The European patients were all compound heterozygous for V529M and another CNGA3 mutation, whereas most of the Arab Muslim and Jewish patients were homozygous for V529M. Haplotype analysis revealed a shared Muslim-Jewish haplotype, which was different from the haplotypes detected in European patients; microsatellite analysis of the surrounding 21.5-cM interval on chromosome 2 revealed a unique and extremely rare haplotype associated with the V529M mutation. The shared mutation was calculated to have arisen about 200 generations earlier, in an ancient common ancestor who lived approximately 5,000 years ago.
In a study of 15 Chinese patients from 10 unrelated families with ACHM, Liang et al. (2015) identified CNGA3 mutations in 13 patients from 8 families.
By whole-exome sequencing (WES) in a man of Senegalese ancestry (CIC02583) with a complex phenotype of congenital nystagmus, photophobia, and progressively worsening visual acuity with only light-perception at age 21 years, with bilaterally constricted visual fields and undetectable responses on full-field electroretinography, Mejecase et al. (2019) identified homozygosity for a 2-bp deletion in the CNGA3 gene (600053.0011). The patient and his 2 older brothers (CIC02584 and CIC02585) exhibited nonsyndromic retinitis pigmentosa (RP93; 619845), and all 3 brothers were compound heterozygous for mutations in the CC2D2A gene (612013.0010-612013.0011). The patient and one of his brothers also had proteinuria (see 618884), and both were compound heterozygous for mutations in the CUBN gene (602997). The respective variants segregated fully with disease in the family, and the authors noted that their case report illustrated the power of WES to elucidate complex phenotypes segregating within a family.
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Wissinger, B., Jagle, H., Kohl, S., Broghammer, M., Baumann, B., Hanna, D. B., Hedels, C., Apfelstedt-Sylla, E., Randazzo, G., Jacobson, S. G., Zrenner, E., Sharpe, L. T. Human rod monochromacy: linkage analysis and mapping of a cone photoreceptor expressed candidate gene on chromosome 2q11. Genomics 51: 325-331, 1998. [PubMed: 9721202] [Full Text: https://doi.org/10.1006/geno.1998.5390]
Wiszniewski, W., Lewis, R. A., Lupski, J. R. Achromatopsia: the CNGB3 p.T383fsX mutation results from a founder effect and is responsible for the visual phenotype in the original report of a uniparental disomy 14. Hum. Genet. 121: 433-439, 2007. [PubMed: 17265047] [Full Text: https://doi.org/10.1007/s00439-006-0314-y]
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Zelinger, L., Greenberg, A., Kohl, S., Banin, E., Sharon, D. An ancient autosomal haplotype bearing a rare achromatopsia-causing founder mutation is shared among Arab Muslims and Oriental Jews. Hum. Genet. 128: 261-267, 2010. [PubMed: 20549516] [Full Text: https://doi.org/10.1007/s00439-010-0846-z]
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