PATERNAL UNIPARENTAL DISOMY FOR CHROMOSOME-1 REVEALED BY MOLECULAR ANALYSIS OF A PATIENT WITH PYCNODYSOSTOSIS

Molecular analysis of a patient affected by the autosomal recessive sk eletal dysplasia, pycnodysostosis (cathepsin K deficiency; MIM 265 800 ), revealed homozygosity for a novel missense mutation (A277V). Since the A277V mutation was carried by the patient's father but not by his mother, who had two normal cathepsin K alleles, paternal uniparental d isomy was suspected. Karyotyping of the patient and of both parents wa s normal, and high-resolution cytogenetic analyses of chromosome 1, to which cathepsin K is mapped, revealed no abnormalities. Evaluation of polymorphic DNA markers spanning chromosome 1 demonstrated that the p atient had inherited two paternal chromosome 1 homologues, whereas all eles for markers from other chromosomes were inherited in a Mendelian fashion. The patient was homoallelic for informative markers mapping n ear the chromosome 1 centromere, but he was heteroallelic for markers near both telomeres, establishing that the paternal uniparental disomy with partial isodisomy was caused by a meiosis II nondisjunction even t. Phenotypically, the patient had normal birth height and weight, had normal psychomotor development at age 7 years, and had only the usual features of pycnodysostosis. This patient represents the first case o f paternal uniparental disomy of chromosome 1 and provides conclusive evidence that paternally derived genes on human chromosome 1 are not i mprinted.