title: Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis.
abstract: Molecular analysis of a patient affected by the autosomal recessive skeletal dysplasia, pycnodysostosis (cathepsin K deficiency; MIM 265800), 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 disomy was suspected. Karyotyping of the patient and of both parents was 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 patient had inherited two paternal chromosome 1 homologues, whereas alleles for markers from other chromosomes were inherited in a Mendelian fashion. The patient was homoallelic for informative markers mapping near 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 event. 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 of paternal uniparental disomy of chromosome 1 and provides conclusive evidence that paternally derived genes on human chromosome 1 are not imprinted.
authors.affiliation: Department of Pediatrics, Mount Sinai School of Medicine, New York, NY, USA. gelb@msvax.mssm.edu
authors.forename: B D
authors.initials: BD
authors.lastname: Gelb
authors.forename: J P
authors.initials: JP
authors.lastname: Willner
authors.forename: T M
authors.initials: TM
authors.lastname: Dunn
authors.forename: N B
authors.initials: NB
authors.lastname: Kardon
authors.forename: A
authors.initials: A
authors.lastname: Verloes
authors.forename: J
authors.initials: J
authors.lastname: Poncin
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000328:Adult; D001848:Bone Diseases, Developmental / Q000235:genetics*; D056657:Cathepsin K; D002403:Cathepsins / Q000172:deficiency* / Q000235:genetics*; D002675:Child, Preschool; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation
chemical_list: D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K