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S. Dubois, M. Giunta, T. Nawar, R. Arseneault, M.-A. Rodrigue, V. Raymond; Concurrent Mutations in Harmonin (USH1C) and Collagen IV (COL4A5), Two Components of the Usher Protein Network, Enhance the Severity of Usher and Alport Syndromes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4087.
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Usher and Alport syndromes are 2 relatively rare multisystemic inherited diseases affecting the ear, eye and kidney. We performed a genotype/phenotype correlation study in a 3 generation French-Canadian family with features compatible with Usher and Alport.
DNA was obtained from 17 persons. Records of 7 affected were revised. Disease haplotypes were established by genotyping markers at USH1C (11p15.1), USH2A (1q41), COL4A3-COL4A4 (2q36) and COL4A5-COL4A6 (Xq22). The 6 genes were screened for mutations by sequencing all their coding exons and splicing junctions.
The proband was a man of the 3rd generation with deafness at young age. At 15 years old, he was diagnosed with Alport. At about 18, he was also diagnosed with severe bilateral uveitis and retinitis pigmentosa, suggesting Usher. The proband’s sister was diagnosed Usher. She did not show any sign of uveitis. Both sibs had normal vestibular functions. The proband’s mother and maternal aunt exhibited, respectively, mild Alport and glomerulonephritis that responded to treatment. A common USH1C disease haplotype was detected in the proband, his sister and 2 parents. DNA sequencing revealed that the proband and his sister were homozygotic carriers of the c.216G4A USH1C founder mutation, also know as the Acadian allele. Both parents were heterozygotic silent carriers of the mutation. The mutation resulted in aberrant splicing and an unstable transcript. A diagnosis of autosomal recessive Usher syndrome was thus made for the proband and his sister. A common COL4A5-COL4A6 disease haplotype was also segregating in the family. Sequencing revealed that the proband, his mother, maternal aunt and maternal grand-mother were carriers of the 421delG COL4A5 mutation. This mutation produced a truncated protein and accounted for X-linked dominant Alport syndrome that led to rapid kidney failure in the hemizygotic proband but only mild effects in the heterozygotic females as they harbored a wild-type allele on their 2nd X.
This is the 1st report of a patient carrying concurrent mutations causing two mendelian syndromes with overlapping features. Increased severity of ocular and kidney symptoms and the uveitis may result from a conjugated mechanism of the 2 mutated proteins, harmonin and collagen IV, on the usher protein network through their interaction with the transmembrane usherin (USH2A) protein.
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