Variant Phenotypes of Incomplete Achromatopsia in Two Cousins with GNAT2 Gene Mutations

Aarhus University, Aarhus, Central Jutland, Denmark
Investigative Ophthalmology & Visual Science (Impact Factor: 3.4). 12/2004; 45(12):4256-62. DOI: 10.1167/iovs.04-0317
Source: PubMed


The present study was designed to elucidate the molecular genetic basis of a congenital stationary cone dysfunction characterized by congenital nystagmus, moderate visual impairment, and markedly disparate color vision deficiencies between two affected cousins.
Ophthalmic examinations with emphasis on color vision and electrophysiology. Molecular genetic analysis of the X-linked cone opsin genes, mutation screening of the CNGA3, CNGB3, and GNAT2 genes, and heterologous splicing experiments.
Whereas the proband was found to carry a homozygous frameshift mutation (Tyr95fs) in GNAT2, her cousin was compound heterozygous for the Tyr95fs and a new intronic mutation c.461 + 24G-->A. Heterologous expression in COS7 cells showed that the latter causes a splicing defect that results in early translation termination. Yet, this mutation is leaky, giving rise to small amounts of correctly spliced transcripts and offer an explanation for the diverging clinical findings in the cousins, one best described as incomplete achromatopsia and the other with oligocone trichromacy.
The cases presented broaden the phenotypic spectrum of GNAT2 mutations and underline the increasing importance of molecular genetics in the clinical diagnosis of atypical ophthalmic phenotypes.


Available from: Thomas Rosenberg
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    • "The Gnat1-KO mouse demonstrated that rod-driven signals require functional GNAT1, and its absence leads to slow degeneration of the photoreceptors (Calvert et al., 2000). GNAT2 encodes the cone version of α-transducin (Morris and Fong, 1993), and mutations in GNAT2 result in complete achromatopsia – i.e. no cone function at all (Kohl et al., 2002 ) – incomplete achromatopsia or extreme redgreen color blindness (protanopia) (Rosenberg et al., 2004). The Gnat2-KO mouse phenotype largely resembled the human disease and revealed that misfolding of the transducin protein results in loss of cone function, opsin mis-localization, retinal remodeling and slow degeneration of photoreceptors (Jobling et al., 2013). "
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    • "A reduced number of foveal cones may be responsible for this disease. So far, mutations in the genes encoding the cone-specific transducin alpha subunit (GNAT2) and the beta 3 subunit of the cyclic nucleotide gated channel (CNGB3) were associated with this form of cone dysfunction (Andersen et al., 2009; Rosenberg et al., 2004). "
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    • "The presentation of incomplete or atypical achromatopsia is similar, except that some color vision and improved acuity are present [7]. Most cases of human achromatopsia have been associated with mutations in three genes that play a major role in the cone phototransduction cascade. "
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