Mutations in hepatocyte nuclear factor-1β and their related phenotypes
Mutations in hepatocyte nuclear factor-1β and their related phenotypes
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DOI：
10.1136/jmg.2005.032854
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发表时间：
2006-01-01
影响因子：
4
通讯作者：
Hattersley, AT
中科院分区：
文献类型：
--
作者：
Edghill, EL;Bingham, C;Hattersley, AT
背景资料：肝细胞核因子-1 β（HNF-1 β）是一种广泛分布的转录因子，在肾脏、胰腺、肝脏和苗勒管的胚胎发育中起关键作用。30例HNF-1 β突变已在肾囊肿和其他肾脏发育障碍、糖尿病、胰腺萎缩、肝功能检查异常和生殖道异常的患者中报道。方法：我们对160例无关的肾脏疾病受试者进行了HNF-1 β基因测序，其中40%有糖尿病个人/家族史。结果：在23/160例受试者（14%）中发现了23种不同的杂合HNF-1 β突变，包括10种新突变（V61 G、V110 G、S148 L、K156 E、Q176 X、R276 Q、S281 fsinsC、R295 P、H324 fsdelCA、Q470 X）。7例（30%）病例被证明是由于从头突变。23例患者中有19例（83%）发现肾囊肿（4例患有肾小球囊性肾病，GCKD），11例（48%）发现糖尿病，而其他3个家族有糖尿病家族史。只有26%的家庭符合年轻人成熟型糖尿病（MODY）的诊断标准，但39%的家庭患有肾囊肿和糖尿病（RCAD）。我们没有发现明确的基因型/表型relationships.Conclusion：我们报告了迄今为止最大的一系列HNF-1 β突变，并确认HNF-1 β突变是肾脏疾病的重要原因。尽管最初将HNF-1 β描述为MODY基因，但通常缺乏糖尿病的个人/家族史，最常见的临床表现是肾囊肿。对于不明原因的肾囊肿（包括GCKD）患者，应考虑进行HNF-1 β突变的分子遗传学检测，特别是当与糖尿病，早发性痛风或子宫异常相关时。
Background: Hepatocyte nuclear factor-1 beta (HNF-1 beta) is a widely distributed transcription factor which plays a critical role in embryonic development of the kidney, pancreas, liver, and Mullerian duct. Thirty HNF-1 beta mutations have been reported in patients with renal cysts and other renal developmental disorders, young-onset diabetes, pancreatic atrophy, abnormal liver function tests, and genital tract abnormalities.Methods: We sequenced the HNF-1 beta gene in 160 unrelated subjects with renal disease, 40% of whom had a personal/ family history of diabetes.Results: Twenty three different heterozygous HNF-1 beta mutations were identified in 23/160 subjects (14%), including 10 novel mutations (V61G, V110G, S148L, K156E, Q176X, R276Q, S281fsinsC, R295P, H324fsdelCA, Q470X). Seven (30%) cases were proven to be due to de novo mutations. Renal cysts were found in 19/23 (83%) patients ( four with glomerulocystic kidney disease, GCKD) and diabetes in 11/ 23 (48%, while three other families had a family history of diabetes. Only 26% of families met diagnostic criteria for maturity-onset diabetes of the young ( MODY) but 39% had renal cysts and diabetes (RCAD). We found no clear genotype/phenotype relationships.Conclusion: We report the largest series to date of HNF-1 beta mutations and confirm HNF-1 beta mutations as an important cause of renal disease. Despite the original description of HNF-1 beta as a MODY gene, a personal/ family history of diabetes is often absent and the most common clinical manifestation is renal cysts. Molecular genetic testing for HNF-1 beta mutations should be considered in patients with unexplained renal cysts ( including GCKD), especially when associated with diabetes, early-onset gout, or uterine abnormalities.