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A. Gal, V. Szabo, H.-Jü. Kreienkamp, T. Rosenberg; p.Gln200Glu, a Putative Constitutively Active Mutant of Rod Alpha-Transducin in Autosomal Dominant Congenital Stationary Night Blindness. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1662. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To define the gene defect causing congenital stationary night blindness (CSNB) in a family with an autosomal dominant (ad) form of the trait. CSNB is a non-progressive Mendelian condition resulting from a functional defect of rod photoreceptors. A small number of unique missense mutations in the genes encoding rhodopsin (RHO), cGMP phosphodiesterase beta-subunit (PDE6B), and transducin alpha-subunit (GNAT1) have been reported to cause adCSNB. Two basic mechanisms of opposite nature have been suggested to explain the phenotype. While the RHO and PDE6B mutations result in constitutively active proteins, the only known adCSNB-associated GNAT1 change (p.Gly38Asp) seems to be a loss-of-function mutation.
The Danish pedigree analysed consists of 9 family members presenting with typical symptoms of CSNB in three generations. In addition to standard ophthalmologic examination, dynamic visual field measurement, colour vision testing, dark adaptometry, and full-field ERG recording were performed.
Linkage analysis with markers corresponding to loci that map close to RHO and PDE6B yielded negative lod scores, making it unlikely that these genes are implicated in this family. In two-point analysis, D3S1289, the locus close to GNAT1, gave positive lod scores with Zmax=1.81 at theta=0.00. We identified a novel heterozygous C to G transversion (c.598C>G) in exon 6 of GNAT1 that encodes a p.Gln200Glu substitution (CAG>GAG) in the evolutionarily conserved Switch 2 region of alpha-transducin. The mutation results in loss of a TseI site and we showed that the c.598C>G mutation was present in all affected family members in heterozygous state. The c.598C>G change was absent from 104 alleles of unaffected and unrelated controls. Computer modeling based on the known crystal structure of transducin suggests that the mutant protein exhibits impaired GTPase activity, thereby leading to constitutive activation of phototransduction. This assumption is in line with previously published in vitro activity data for a recombinant mutant protein.
Our findings support the general observation that inappropriately activating mutants of various members of the rod phototransduction cascade represent the major molecular cause of adCSNB.
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