![]() The researchers demonstrated that the precise type of genetic mutation (i.e. One cousin was found to carry a homozygous frameshift mutation (Tyr95fs) whereas the other was compound heterozygous for the Tyr95fs and a new intronic mutation (c.461 + 24G→A). in 2004, reporting on two cousins with GNAT2 mutations, further elucidated these genetic discrepancies. These findings have been replicated in patients affected by a GNAT2 mutation. Therefore, a CNGA3 mutation may not always cause complete absence of cone function. Additionally, CNGA3 mutations were occasionally found in patients with severe progressive cone dystrophy. CNGA3 mutations were detected in both complete and incomplete achromatopsia. examined patients with CNGA3 mutations, a gene originally felt to be responsible for the autosomal recessive complete form of the disease. A study of 258 patients by Wissinger et al. The association between mutations in these five specific genes and a complete or incomplete achromatopsia phenotype does not appear to directly correlate. Finally, the alpha and beta subunits of the cyclic nucleotide-gated ion channels on the plasma membrane of outer cone segments, CNGA3 (ACHM2) and CNGB3 (ACHM3), are activated, leading to membrane polarization changes l. Activated transducin will bind to the PDE6C protein and the inhibitory gamma-subunit PDE6H (ACHM6). When cones are exposed to light stimuli, excited pigment molecules undergo energy exchange at the alpha subunit of the transducin protein GNAT2 (ACHM4). These five genes code for proteins required for critical steps of phototransduction in the cone photoreceptors. The potential for the treatment of achromatopsia in humans with gene therapy shows great promise. Genetic understanding and disease characterization of achromatopsia continues to evolve, as do gene therapy tools and animal models. Two clinical trials are under way: one to better characterize humans with achromatopsia and another to study a ciliary neurotrophic factor (CNTF) implant as a treatment for patients with the CNGB3 mutation. A sheep CNGA3 model has also been characterized. Recent findingsīuilding on prior success with adeno-associated virus (AAV) therapy in mice models for achromatopsia with mutations in the CNGB3, CNGA3, or GNAT2 genes, multiple cone-specific promoters have recently been developed and shown success in mice and nonhuman primates. Specifically, this article will describe recent advances in gene therapy in animal models, clinical features in human, and barriers to human translation. The purposes of this article are to examine the literature published on achromatopsia and provide a comprehensive review of the clinical disease, genetic characteristics, and potential for therapy.
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