A CACNA1D mutation in a patient with persistent hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotonia.
A CACNA1D mutation in a patient with persistent hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotonia.
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DOI：
10.1111/pedi.12512
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发表时间：
2017-06
影响因子：
3.4
通讯作者：
Ellard S
中科院分区：
文献类型：
--
作者：
Flanagan SE;Vairo F;Johnson MB;Caswell R;Laver TW;Lango Allen H;Hussain K;Ellard S
先天性高胰岛素性低血糖（HH）可以单独发生，也可以作为更广泛综合征的一部分出现。对于大约40%-50%的患有这种疾病的个体，已知HH基因的序列分析确定了致病突变。确定其余病例的潜在遗传病因非常重要，因为遗传诊断将为复发风险提供信息，可以指导医疗管理，并将为β细胞生理学提供有价值的见解。我们对一名患有持续性二氮嗪反应性HH、轻度主动脉瓣关闭不全、重度张力减退和发育迟缓的儿童以及未受影响的父母的外显子组进行了测序。该分析确定了先证者CACNA 1D基因中的一个从头突变p.G403D。CACNA 1D编码胰腺β细胞中的主要L型电压门控钙通道，这是胰岛素分泌途径的关键组成部分。先前已将p.G403D突变报告为原发性醛固酮增多症、神经肌肉异常和一过性低血糖个体的激活突变。对另外60例HH患者的CACNA 1D基因进行序列分析，未发现致病性突变。在第二例先天性HH患者中鉴定出激活的CACNA 1D突变，证实了CACNA 1D突变在这种疾病中的病因作用。基因诊断是重要的，因为用钙通道阻滞剂治疗可能是该患者的医疗管理的一种选择。
Congenital hyperinsulinaemic hypoglycaemia (HH) can occur in isolation or it may present as part of a wider syndrome. For approximately 40%‐50% of individuals with this condition, sequence analysis of the known HH genes identifies a causative mutation. Identifying the underlying genetic aetiology in the remaining cases is important as a genetic diagnosis will inform on recurrence risk, may guide medical management and will provide valuable insights into β‐cell physiology. We sequenced the exome of a child with persistent diazoxide‐responsive HH, mild aortic insufficiency, severe hypotonia, and developmental delay as well as the unaffected parents. This analysis identified a de novo mutation, p.G403D, in the proband's CACNA1D gene. CACNA1D encodes the main L‐type voltage‐gated calcium channel in the pancreatic β‐cell, a key component of the insulin secretion pathway. The p.G403D mutation had been reported previously as an activating mutation in an individual with primary hyper‐aldosteronism, neuromuscular abnormalities, and transient hypoglycaemia. Sequence analysis of the CACNA1D gene in 60 further cases with HH did not identify a pathogenic mutation. Identification of an activating CACNA1D mutation in a second patient with congenital HH confirms the aetiological role of CACNA1D mutations in this disorder. A genetic diagnosis is important as treatment with a calcium channel blocker may be an option for the medical management of this patient.