Mutations in the Cone Photoreceptor G-Protein α-Subunit Gene GNAT2 in Patients with Achromatopsia

Kohl, Susanne; Baumann, Britta; Rosenberg, Thomas; Kellner, Ulrich; Lorenz, Birgit; Vadalà, Maria; Jacobson, Samuel G.; Wissinger, Bernd

doi:10.1086/341835

Cited by 234 publications

(166 citation statements)

References 16 publications

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“…As with all the GNAT2 mutations observed, 10,11,30 the p.Arg313X results in a premature translation termination. It is located in a receptor contact site a4-b6 loop of Ga transducin 31 leading to a truncated alpha G-transducin short of 41 amino acids in the carboxy terminal region.…”

Section: Discussionmentioning

confidence: 60%

“…Until now two sporadic GNAT2 achromatopsia cases and four patients belonging to two families were been reported worldwide. 11 A total of 12 individuals were diagnosed as having total color blindness and others were suspected to be affected based on familial history. The relatively high number of affected individuals is likely the result of nonrandom mating in a highly endogamous family.…”

Section: Discussionmentioning

confidence: 99%

“…The GNAT2 gene encoding the alpha subunit of cone transducin G protein has been reported as the third most frequently affected gene, responsible for 2% of achromatopsia cases. 10,11 Recently, the Pde6c gene has been involved in achromatopsia in the murine cpfl1 mutant. Consequently, it has been shown that the human ortholog PDE6C, located at 10q24, was also linked to achromatopsia.…”

Section: Introductionmentioning

confidence: 99%

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

Ouechtati

Merdassi²,

Bouyacoub

et al. 2010

J Hum Genet

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Complete achromatopsia is a rare autosomal recessive disease associated with CNGA3, CNGB3, GNAT2 and PDE6C mutations. This retinal disorder is characterized by complete loss of color discrimination due to the absence or alteration of the cones function. The purpose of the present study was the clinical and the genetic characterization of achromatopsia in a large consanguineous Tunisian family. Ophthalmic evaluation included a full clinical examination, color vision testing and electroretinography. Linkage analysis using microsatellite markers flanking CNGA3, CNGB3, GNAT2 and PDE6C genes was performed. Mutations were screened by direct sequencing. A total of 12 individuals were diagnosed with congenital complete achromatopsia. They are members of six nuclear consanguineous families belonging to the same large consanguineous family. Linkage analysis revealed linkage to GNAT2. Mutational screening of GNAT2 revealed three intronic variations c.119À69G4C, c.161+66A4T and c.875À31G4C that co-segregated with a novel mutation p.R313X. An identical GNAT2 haplotype segregating with this mutation was identified, indicating a founder mutation. All patients were homozygous for the p.R313X mutation. This is the first report of the clinical and genetic investigation of complete achromatopsia in North Africa and the largest family with recessive achromatopsia involving GNAT2; thus, providing a unique opportunity for genotype-phenotype correlation for this extremely rare condition.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Ouechtati

Merdassi²,

Bouyacoub

et al. 2010

J Hum Genet

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“…Retinal cone photoreceptors can be the primary target of genetic diseases such as achromatopsia, [1][2][3][4] cone or cone/ rod dystrophies (see RetNet for summary: http://www. sph.uth.tmc.edu/RetNet/).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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Specific cone-directed therapy is of high priority in the treatment of human hereditary retinal diseases. However, not much information exists about the specific targeting of photoreceptor subclasses. Three versions of the human red cone opsin promoter (PR0.5, 3LCR-PR0.5 and PR2.1), and the human blue cone opsin promoter HB569, were evaluated for their specificity and robustness in targeting green fluorescent protein (GFP) gene expression to subclasses of cones in the canine retina when used in recombinant adeno-associated viral vectors of serotype 5. The vectors were administered by subretinal injection. The promoter PR2.1 led to most effective and specific expression of GFP in the long-and medium-wavelength-absorbing cones (L/M cones) of normal and diseased retinas. The PR0.5 promoter was not effective. Adding three copies of the 35-bp LCR in front of PR0.5 lead to weak GFP expression in L/M cones. The HB569 promoter was not specific, and GFP was expressed in a few L/M cones, some rods and the retinal pigment epithelium. These results suggest that L/M cones, the predominant class of cone photoreceptors in the retinas of dogs and most mammalian species can be successfully targeted using the human red cone opsin promoter.

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“…Cone degeneration may or may not be associated with the disease. In humans, mutations in the cyclic nucleotide gated channel ␣ and ␤ subunits as well as cone-specific version of transducin are known to cause this disease (Kohl et al, 2000(Kohl et al, , 2002Johnson et al, 2004). Furthermore, a very recent preliminary report indicates that mutations in cone-specific pde6 can be identified in families with achromatopsia (Wissinger et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

A Mutation in the Cone-Specificpde6Gene Causes Rapid Cone Photoreceptor Degeneration in Zebrafish

Stearns¹,

Evangelista²,

Fadool³

et al. 2007

J. Neurosci.

110

129

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Photoreceptor degeneration is a common cause of inherited blindness worldwide. We have identified a blind zebrafish mutant with rapid degeneration of cone photoreceptors caused by a mutation in the cone phosphodiesterase c ( pde6c) gene, a key regulatory component in cone phototransduction. Some rods also degenerate, primarily in areas with a low density of rods. Rod photoreceptors in areas of the retina that always have a high density of rods are protected from degeneration. Our findings demonstrate that, analogous to what happens to rod photoreceptors in the rd1 mouse model, loss of cone phosphodiesterase leads to rapid degeneration of cone photoreceptors. Furthermore, we propose that cell density plays a key role in determining whether rod photoreceptors degenerate as a secondary consequence to cone degeneration. Our zebrafish mutant serves as a model for developing therapeutic treatments for photoreceptor degeneration in humans.

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Mutations in the Cone Photoreceptor G-Protein α-Subunit Gene GNAT2 in Patients with Achromatopsia

Cited by 234 publications

References 16 publications

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

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

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

A Mutation in the Cone-Specificpde6Gene Causes Rapid Cone Photoreceptor Degeneration in Zebrafish

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