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C Rivolta, EL Berson, TP Dryja; Uniparental Primary Heterodisomy with Bitelomeric Isodisomyh of Chromosome 1 in a Patient with Onsyndromic Retinitis Pigmentosa and a Mutation in the Usher Syndrome Gene USH2A . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2401.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To understand the genetic mechanisms responsible for homozygosity of an USH2A mutation in a patient and her second cousin, both with nonsyndromic, recessive retinitis pigmentosa (RP). Methods: Direct DNA sequencing of the USH2A coding sequence and microsatellite analysis of polymorphic markers from chromosome 1 (chr. 1) and other chromosomes. Results: The index patient was homozygous for the mutation Cys759Phe in the USH2A gene on chr. 1q, a previously reported cause of nonsyndromic RP. Her father was a heterozygote, but her mother did not carry the mutation. Analysis of markers from chromosomes other than chr. 1 provided strong evidence that that the designated parents were the biological parents. Evaluation of markers from chr. 1 revealed that the patient had inherited two copies of chr. 1 from her father and none from her mother. The chr. 1's were heteroallelic over a region extending from the centromere to the proximal short and long arms. The distal short and long arms, including the region of 1q with the mutant USH2A allele, were homoallelic. A paternal second-cousin of the patient also had RP and also had the identical mutation in the same codon of USH2A. However, the analysis of an isocoding polymorphism 20 bp away and of closely linked microsatellite markers in this cousin and in family members indicated that the two mutant alleles arose independently. Conclusions: The index patient is an example of uniparental primary heterodisomy, a term indicating that the uniparentally derived chromosomes are derived from both homologues of the transmitting parent. Meiotic recombination events during meiosis I explain the regions of homozygosity in the distal short and long arms. A few other examples of uniparental disomy in patients with recessive ophthalmic diseases have been reported, and additional examples are sure to be discovered as the genes for ophthalmic diseases become available for analysis. The occurrence of the same mutation in the index patient's cousin is entirely by chance.
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