Marcus S, Steen A M, Andersson B, Lambert B, Kristoffersson U, Francke U
Department of Clinical Genetics, Karolinska Institute, Stockholm, Sweden.
Hum Genet. 1992 Jun;89(4):395-400. doi: 10.1007/BF00194310.
A nonsense mutation at the CpG-site in the codon for Arg(169) in the gene for hypoxanthine phosphoribosyltransferase (hprt) was identified by genomic polymerase chain reaction (PCR) and DNA sequencing in cultured fibroblasts from two brothers with Lesch Nyhan's syndrome. The recurrence of mutation at this CpG-site in several unrelated Lesch-Nyhan families suggests that deamination of 5-methylcytosine is a possible mechanism for mutagenesis. The level of hprt-mRNA in the fibroblasts of the patients was similar to that in healthy controls, whereas hprt-enzyme activity was not detectable. The mutation in this family was also identified in five female relatives and prenatally in a male fetus. Unexpectedly, results from hair follicle analyses and fibroblast selection studies in 8-azaguanine and 6-thioguanine medium showed a non-carrier phenotype in three of the female heterozygotes, whereas X-inactivation mosaicism was demonstrated in one heterozygote. A possible explanation for the apparent non-random X-inactivation in this family is the co-existence of the hprt mutation with an undefined X-linked lethal mutation. This observation is of practical relevance for carrier detection in other Lesch-Nyhan families.
通过基因组聚合酶链反应（PCR）和DNA测序，在两名患有莱施-奈恩综合征的兄弟的培养成纤维细胞中，鉴定出次黄嘌呤磷酸核糖基转移酶（hprt）基因中编码精氨酸（169）的密码子的CpG位点存在无义突变。在几个不相关的莱施-奈恩家族中，该CpG位点的突变复发表明5-甲基胞嘧啶的脱氨作用可能是诱变的一种机制。患者成纤维细胞中hprt - mRNA的水平与健康对照相似，而hprt酶活性无法检测到。在该家族中，5名女性亲属也检测到该突变，一名男性胎儿在产前也检测到该突变。出乎意料的是，在8-氮杂鸟嘌呤和6-硫鸟嘌呤培养基中进行的毛囊分析和成纤维细胞选择研究结果显示，三名女性杂合子表现为非携带者表型，而在一名杂合子中发现了X染色体失活嵌合现象。该家族中明显的非随机X染色体失活的一个可能解释是，hprt突变与一个未确定的X连锁致死突变共存。这一观察结果对其他莱施-奈恩家族的携带者检测具有实际意义。
