CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia

Abstract

Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (o0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum and prevalence of CNGB3 gene mutations in a cohort of 341 independent patients with achromatopsia. In 163 patients, CNGB3 mutations could be identified. A total of 105 achromats carried apparent homozygous mutations, 44 were compound (double) heterozygotes, and 14 patients had only a single mutant allele. The derived CNGB3 mutation spectrum comprises 28 different mutations including 12 nonsense mutations, eight insertions and/or deletions, five putative splice site mutations, and three missense mutations. Thus, the majority of mutations in the CNGB3 gene result in significantly altered and/or truncated polypeptides. Several mutations were found recurrently, in particular a 1 bp deletion, c.1148delC, which accounts for over 70% of all CNGB3 mutant alleles. In conclusion, mutations in the CNGB3 gene are responsible for approximately 50% of all patients with achromatopsia. This indicates that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent.

Targeting gene expression to cones with human cone opsin promoters in recombinant AAV

“…4 CNGB3 is also mutated in about 50% of human patients with achromatopsia. 17 On the other hand, XLPRA is caused by microdeletions in exon ORF15 of RPGR, and the mutation causing a frameshift has a severe, and aggressive early-onset cone/rod disease phenotype similar to what is found in RPGR/XLRP patients. 6,18 Previous studies have shown that sequences upstream of the human red or long wavelength (L) opsin gene contain a core promoter with a locus control region (LCR) that confers expression in cones of transgenic mice.…”

Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene

“…[22][23][24][25][26] Compared with the other two genes known to cause achromatopsia CNGA3 and CNGB3, GNAT2 is only a minor achromatopsia locus, which account for 2% of the cases. 7 As this is the largest sibship affected with GNAT2 achromatopsia, this family gave a unique opportunity for phenotype-genotype analysis and comparison to other complete achromatopsia subtypes. Although some CNGB3 affected subjects and carriers presented a macular atrophy and peripheral granularity, respectively, 27 no macular atrophy was identified in ACH-G patients' and carriers' fundi.…”

“…[3][4][5][6] Rod monochromacy is inherited as an autosomal recessive trait with complete penetrance and is associated with mutations in four different genes. Two genes, CNGA3 and CNGB3, which are more frequently associated to achromatopsia, 7 encode the alpha and beta subunits of cyclic guanosine monophosphate-gated cation channel in cone cells, respectively. 8,9 This channel is involved in cone membrane hyperpolarization during visual transduction.…”

Safety and Efficacy Evaluation of rAAV2tYF-PR1.7-hCNGA3 Vector Delivered by Subretinal Injection in CNGA3 Mutant Achromatopsia Sheep

“…2,3 In other populations, CNGA3-associated ACHM seems to be more prevalent. 4,5 CNGA3 and CNGB3 mutations result in a loss of cone photoreceptor function in humans and in animals with mutations in the homologous genes.…”