Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis
Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis
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DOI：
10.1086/301795
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发表时间：
1998-04-01
影响因子：
9.8
通讯作者：
Desnick, RJ
中科院分区：
文献类型：
--
作者：
Gelb, BD;Willner, JP;Desnick, RJ
对患有常染色体隐性遗传性骨骼发育不良、致密性骨质增生（组织蛋白酶 K 缺乏；MIM 265 800）的患者进行的分子分析揭示了一种新的错义突变 (A277V) 的纯合性。由于 A277V 突变由患者的父亲携带，而其母亲则没有，而母亲有两个正常的组织蛋白酶 K 等位基因，因此怀疑父亲单亲二体性。患者和父母双方的核型分析均正常，组织蛋白酶 K 定位的 1 号染色体的高分辨率细胞遗传学分析未发现异常。对跨越 1 号染色体的多态性 DNA 标记的评估表明，患者遗传了两个父系 1 号染色体同源物，而来自其他染色体的标记的等位基因则以孟德尔方式遗传。该患者在 1 号染色体着丝粒附近的信息性标记物上是同等位基因，但在两个端粒附近的标记物上是异等位基因，这表明具有部分等二体性的父本单亲二体性是由减数分裂 II 不分离事件引起的。从表型上看，患者出生时身高和体重正常，7岁时精神运动发育正常，仅具有致密性骨质增生的常见特征。该患者代表了第一例 1 号染色体父系单亲二倍体病例，并提供了确凿的证据，证明人类 1 号染色体上的父系衍生基因没有被印记。
Molecular analysis of a patient affected by the autosomal recessive skeletal 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 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.