Clinical spectrum associated with hepatocyte nuclear factor-1β mutations
Clinical spectrum associated with hepatocyte nuclear factor-1β mutations
复制标题
DOI：
10.7326/0003-4819-140-7-200404060-00009
复制
发表时间：
2004-04-06
影响因子：
39.2
通讯作者：
Timsit, J
中科院分区：
文献类型：
--
作者：
Bellanné-Chantelot, C;Chauveau, D;Timsit, J
背景资料：青年5型成熟型糖尿病（MODY 5）是一种显性遗传性糖尿病和肾病，与肝细胞核因子-1 β（HNF-1 β）基因突变有关，主要产生截短蛋白。各种表型，包括泌尿生殖系统畸形，都与HNF-1 β突变有关。目的：描述13例HNF-1 β新突变患者的临床和遗传学表现。设计：多中心，描述性研究。设置：2个糖尿病科，1个内科和1个肾病科。参与者：8名在40岁之前被诊断为糖尿病的先证者和5名后代，这些先证者是独立于糖尿病家族史而选择的非糖尿病肾病。糖尿病特征、肾功能和结构、生殖道异常、胰腺结构、胰岛素分泌、胰腺外分泌功能和肝脏检查结果。所有突变，包括5个错义突变，发现在DNA结合域。在4个家系中观察到突变和MODY 5表型的共分离。在2个家系中证实了新发突变的发生。13名突变携带者中有10名患有糖尿病。在5名参与者中临床上明显，并在5名参与者中通过19至38岁的筛选发现。6例先证者中5例出现胰腺萎缩，7例先证者中6例出现胰腺外分泌功能不全。9例患者在18至41岁时出现肾脏受累，包括结构改变和缓慢进行性肾衰竭。超声检查发现3例胎儿肾脏发育不良，随后出现一过性新生儿肾功能衰竭。生殖道异常存在于5先证者和肝酶水平异常11 13 patients.Limitations：由于研究规模小，而不是populationbased，它不能估计MODY 5的患病率。其他表型可能与HNF-1 β mutations.Conclusions：年轻的5型糖尿病成熟期发病包括广泛的临床谱。即使没有糖尿病家族史，在患有糖尿病和缓慢进展的非糖尿病肾病的非肥胖患者中，特别是当存在胰腺萎缩或生殖器异常时，也需要分析HNF-1 β的突变。
Background: maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1beta (HNF-1beta) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1beta mutations.Objective: To describe clinical and genetic findings in 13 patients with 8 novel HNF-1beta mutations.Design: Multicenter, descriptive study.Setting: 2 departments of diabetes, 1 department of internal medicine, and 1 department of nephrology.Participants: 8 probands with diabetes diagnosed before 40 years of age and nondiabetic kidney disease who were selected independent of their family history of diabetes, and 5 offspring.Measurements: Characteristics of diabetes, renal function and structure, genital tract abnormalities, pancreas structure, insulin secretion, exocrine pancreas function, and liver test results.Results: All mutations, including 5 missense changes, were found in the DNA-binding domain. Cosegregation of the mutation and MODY5 phenotype was observed in 4 families. Occurrence of a de novo mutation was demonstrated in 2 families. Diabetes was present in 10 of 13 mutation carriers. It was clinically overt in 5 participants and found by screening at age 19 to 38 years in 5 participants. Pancreas atrophy was observed in 5 of 6 probands, and pancreas exocrine insufficiency was observed in 6 of 7 probands. Renal involvement, consisting of structural changes and slowly progressive renal failure, was recognized in 9 patients at 18 to 41 years of age. Dysplastic kidneys were found by ultrasonography in 3 fetuses who subsequently showed transient neonatal renal failure. Genital tract abnormalities were present in 5 probands and liver enzyme levels were abnormal in 11 of 13 patients.Limitations: since the study was small and not populationbased, it could not estimate the prevalence of MODY5. Other phenotypes might be associated with HNF-1beta mutations.Conclusions: Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1beta is warranted, even without a family history of diabetes, in nonobese patients with diabetes and slowly progressive nondiabetic nephropathy, particularly when pancreatic atrophy or genital abnormalities are present.