Mechanisms for the Occurrence of Three Uniparental Disomies Associated with Abnormal Phenotypes

Results of a molecular-genetic study on the mechanism of uniparental disomy (UPD) in three individuals are reported. Case 1 was a physically normal adult whose Rh blood-type showed mosaicism of two phenotypes, D+ (or D/D genotype) and D- (or d/d genotype), while his father and mother were a D/d heterozygote and a D/D homozygote respectively. Allele-typing of his peripheral blood leukocytes and buccal membrane cells using polymorphic DNA markers on chromosome 1 revealed both paternal and maternal alleles, but demonstrated paternal uniparental transmissions of alleles in the monoclonal B-lymphocytes and in hair-root cells from various body regions. The results indicate that he had two cell lines each with paternal UPD1 and maternal UPD1. Only a plausible mechanism for the mosaicism includes abnormal segregation at first mitosis, where both chromatids of each homologs 1 migrated together to the same direction, resulting in two daughter cells having D/D and d/d genotypes. This sort of cell division has hitherto been undescribed in man. Case 2 was a Silver-Russell syndrome patient with a mosaic 46, XX47, XX, +r (7) karyotype. Allele-typing with chromosome 7 markers revealed that she inherited maternal uniparental alleles at telomeric regions of the chromosome but biparental alleles at the centromeric region, the result indicating that the two normal chromosomes 7 were of maternal UPD and the ring chromosome 7 was of paternal origin. A likely mechanism for her UPD7 is monosomy duplication, followed by somatic loss of the ring chromosome. The finding also indicates that the putative SRS locus can be ruled out from the centromeric region, 7p13-qll. Case 3 had intrauterine growth retardation and a 45, XY, i (14) karyotype. Alleletyping revealed maternal uniparental transmissions of alleles at both centromeric and telomeric regions of chromosome 14, but showed biparental alleles at other regions. The results indicate that the isochromosome was of maternal UPD and may have arisen through gametic complementation mechanism