Genetic investigation in an Italian child with an unusual association of atrial septal defect, attributable to a new familial GATA4 gene mutation, and neonatal diabetes due to pancreatic agenesis
Genetic investigation in an Italian child with an unusual association of atrial septal defect, attributable to a new familial GATA4 gene mutation, and neonatal diabetes due to pancreatic agenesis
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DOI：
10.1111/j.1464-5491.2010.03046.x
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发表时间：
2010-10-01
影响因子：
3.5
通讯作者：
Ravazzolo, R.
中科院分区：
文献类型：
--
作者：
D'Amato, E.;Giacopelli, F.;Ravazzolo, R.
目的 永久性新生儿糖尿病是一种罕见疾病，每 300 000-400 000 名活产婴儿中就有 1 人受到影响；只有 60% 的病例才有可能识别出遗传缺陷。胰腺发育不全的情况更为罕见。目前已知只有两个基因可以决定这种表型：PDX-1 和 PTF1A。先天性心脏缺陷是最常见的发育异常之一，影响 1% 的新生儿，而 GATA4 基因与这些疾病的关系较少。对一名患有胰腺发育不全和房间隔缺损的意大利儿童进行了基因研究，以阐明这两种病理的关联是否是偶然的，或者代表了一种新的胰腺/心脏综合征。方法一组胰腺发育基因，包括 GCK、Kir6.2、PTF1A、PDX-1、HNF-1A、NgN3、SOX17、 筛选SOX7、SOX9、INS、HNF1-B 和SUR1 加GATA4 基因以表征胰腺发育不全和心脏缺陷。结果导致永久性新生儿糖尿病的基因筛选结果为阴性。检测到 GATA4 (c1512C>T) 中的新突变，功能表征证实该蛋白活性降低。在家族成员中，GATA4 突变与心脏表型共分离，但与胰腺发育不全无关。 结论 我们描述了胰腺发育不全与相关心脏缺陷和 GATA4 基因突变的第一份报告。我们无法确定 GATA4 突变是胰腺发育不全的原因，并且进一步的遗传学研究未能成功检测胰腺发育不全的遗传原因。我们的结论是，这两种病症可归因于两个独立事件。
Aims Permanent neonatal diabetes is a rare condition affecting 1 in 300 000-400 000 live births; only in 60% of cases it is possible to identify the genetic defect. The condition of pancreatic agenesis is rarer still. Only two genes are known to determine this phenotype: PDX-1 and PTF1A. Congenital heart defects are among the most common developmental anomalies, affecting 1% of new borns, and the GATA4 gene is less frequently involved in these disorders. An Italian child with pancreatic agenesis and an atrial septal defect was genetically investigated to elucidate whether the association of the two pathologies was casual, or represented a new pancreatic/cardiac syndrome.Methods A panel of pancreas development genes, including GCK, Kir6.2, PTF1A, PDX-1, HNF-1A, NgN3, SOX17, SOX7, SOX9, INS, HNF1-B and SUR1 plus the GATA4 gene, were screened for characterization of pancreatic agenesis and cardiac defect.Results Screening for genes causing permanent neonatal diabetes was negative. A novel mutation in GATA4 (c1512C>T) was detected and functional characterization confirmed a reduced activity of the protein. In the family members, the GATA4 mutation co-segregates with a cardiac phenotype, but not with pancreatic agenesis.Conclusions We describe the first report of pancretic agenesis with an associated cardiac defect and a mutation in the GATA4 gene. We could not establish that the GATA4 mutation was causative for pancreatic agenesis and further genetic investigation to detect the genetic cause of the pancreas agenesis was unsuccessful. We conclude that, the two pathologies are attributable to two independent events.