Genetic sequencing confirmed a homozygous R565Q missense mutation in the catalytic domain of PDE6C, a cone-specific phototransduction enzyme associated with achromatopsia in humans.
Our study significantly contributes to the mutation spectrum of PDE6C and allows for a realistic estimate of the prevalence of PDE6C mutations in ACHM since our entire ACHM cohort comprises 1,074 independent families.
We uncovered two mechanisms of PDE6C mutations underlying ACHM: (a) folding defects leading to expression of catalytically inactive proteins and (b) markedly diminished ability of Pγ to co-chaperone mutant PDE6C proteins thereby dramatically reducing the levels of functional enzyme.
Here we present the results of a comprehensive study on PDE6C mutations including the mutation spectrum, its prevalence in a large cohort of ACHM/cone dysfunction patients, the clinical phenotype and the functional characterization of mutant PDE6C proteins.
Moreover, we show that the spontaneous mouse mutant cpfl1 that features a lack of cone function and rapid degeneration of the cone photoreceptors represents a homologous mouse model for PDE6C associated achromatopsia.
All three novel linked regions contain strong candidate genes, especially CNGB3 on 8q21.3, which has been shown to affect photoreceptors and cause complete color blindness.
This implicates ATF6 as having a major role in cone development and suggests that at least a subset of subjects with ATF6-ACHM have markedly fewer cellular targets for cone-directed gene therapies than do subjects with CNGA3- or CNGB3-ACHM.
So far, CNGA3 mutations are not only one of the most common causes of achromatopsia and cone dystrophy or cone-rod dystrophy but also one of the most commonly mutated genes among various forms of retinopathy.
The purpose of this study was to examine the toxicity and side effects of a recombinant adeno-associated virus 8 (AAV8) vector, aimed to treat cyclic nucleotide gated channel alpha 3 (<i>CNGA3</i>)-linked achromatopsia, after a single subretinal administration in cynomolgus macaques.
Whole exome sequencing (WES) applied to the family identified compound heterozygous variants in CC2D2A (c.2774G>C p.(Arg925Pro); c.4730_4731delinsTGTATAp.(Ala1577Valfs*5)) in the three brothers with a homozygous deletion in CNGA3 (c.1235_1236delp.(Glu412Valfs*6)) in the youngest correcting his diagnosis to achromatopsia plus RCD.
Mutations in CNGA3 and CNGB3, the genes encoding the subunits of the tetrameric cone photoreceptor cyclic nucleotide-gated ion channel, cause achromatopsia, a congenital retinal disorder characterized by loss of cone function.