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.
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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). "
"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). "
[Show abstract][Hide abstract]ABSTRACT: During the last two to three decades, a large body of work has revealed the molecular basis of many human disorders, including retinal and vitreoretinal degenerations and dysfunctions. Although belonging to the group of orphan diseases, they affect probably more than two million people worldwide. Most excitingly, treatment of a particular form of congenital retinal degeneration is now possible. A major advantage for treatment is the unique structure and accessibility of the eye and its different components, including the vitreous and retina. Knowledge of the many different eye diseases affecting retinal structure and function (night and colour blindness, retinitis pigmentosa, cone and cone rod dystrophies, photoreceptor dysfunctions, as well as vitreoretinal traits) is critical for future therapeutic development. We have attempted to present a comprehensive picture of these disorders, including biological, clinical, genetic and molecular information. The structural organization of the review leads the reader through non-syndromic and syndromic forms of (i) rod dominated diseases, (ii) cone dominated diseases, (iii) generalized retinal degenerations and (iv) vitreoretinal disorders, caused by mutations in more than 165 genes. Clinical variability and genetic heterogeneity have an important impact on genetic testing and counselling of affected families. As phenotypes do not always correlate with the respective genotypes, it is of utmost importance that clinicians, geneticists, counsellors, diagnostic laboratories and basic researchers understand the relationships between phenotypic manifestations and specific genes, as well as mutations and pathophysiologic mechanisms. We discuss future perspectives.
Full-text · Article · Mar 2010 · Progress in Retinal and Eye Research
"The presentation of incomplete or atypical achromatopsia is similar, except that some color vision and improved acuity are present . Most cases of human achromatopsia have been associated with mutations in three genes that play a major role in the cone phototransduction cascade. "
[Show abstract][Hide abstract]ABSTRACT: Lambs with congenital day blindness show diminished cone function, which is characteristic of achromatopsia, a congenital disorder described in humans and dogs. To identify gene(s) associated with sheep day blindness, we investigated mutations in the CNGA3, CNGB3, and GNAT2 genes which have been associated with achromatopsia. Sequencing the coding regions of those genes from four affected and eight non-affected lambs showed that all affected lambs were homozygous for a mutation in the CNGA3 gene that changes amino acid R236 to a stop codon. By PCR-RFLP-based testing, homozygosity for the stop codon mutation was detected in another 19 affected lambs. Non-affected individuals (n=386) were non-carriers or heterozygous for the mutation. While a selection program has been launched to eradicate the day blindness mutation from Improved Awassi flocks, a breeding nucleus of day-blind sheep has been established to serve as animal models for studying human achromatopsia.