Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys:: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1β gene due to germline mosaicism
Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys:: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1β gene due to germline mosaicism
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DOI：
10.1210/jc.2003-031828
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发表时间：
2004-06-01
影响因子：
5.8
通讯作者：
Nakahata, T
中科院分区：
文献类型：
--
作者：
Yorifuji, T;Kurokawa, K;Nakahata, T
已知编码肝细胞核因子 1β (HNF-1β) 的基因突变会导致一种青少年发病型糖尿病 (MODY5)，其通常特征是与肾囊肿相关的显性遗传性青春期发病糖尿病。然而，本报告描述了两名同胞中 HNF-1beta 基因 S148W (C443G) 的新型错义突变复发，其中一名患有新生儿糖尿病，另一名患有新生儿多囊、发育不良的肾脏，导致早期肾衰竭。前者仅有少数肾小囊肿，肾功能正常，后者仅出现短暂的高血糖，随后自行消退。有趣的是，父母双方在临床上均未受影响，PCR限制性片段长度多态性分析显示母亲是正常和突变HNF-1β的低水平嵌合体，这表明复发是由种系嵌合体引起的。这是首次报道由 HNF-1beta 基因突变引起的永久性新生儿糖尿病，也是首次报道该基因的种系嵌合体。此外，这里描述的两个案例表明，遗传或环境等其他因素可能对 HNF-1beta 突变的表型表达产生显着影响。
Mutations in the gene coding for hepatocyte nuclear factor-1beta (HNF-1beta) have been known to cause a form of maturity-onset diabetes of the young (MODY5), which is usually characterized by dominantly inherited adolescence-onset diabetes mellitus associated with renal cysts. This report, however, describes recurrence of a novel missense mutation in the HNF-1beta gene, S148W (C443G), in two sibs, one with neonatal diabetes mellitus and the other with neonatal polycystic, dysplastic kidneys leading to early renal failure. The former patient had only a few small renal cysts with normal renal functions, and the latter had only a transient episode of hyperglycemia, which resolved spontaneously. Interestingly, both parents were clinically unaffected, and PCR restriction fragment length polymorphism analysis showed that the mother was a low-level mosaic of normal and mutant HNF-1beta, which suggested that the recurrence was caused by germline mosaicism. This is the first report of permanent neonatal diabetes mellitus caused by a mutation of the HNF-1beta gene as well as the first report of germline mosaicism of this gene. In addition, the two cases described here show that additional factors, genetic or environmental, can have a significant influence on the phenotypic expression of HNF-1beta mutations.