Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour
Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour
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DOI：
10.1093/hmg/ddv054
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发表时间：
2015-05-15
影响因子：
3.5
通讯作者：
Benitez, Javier
中科院分区：
文献类型：
--
作者：
Calvete, Oriol;Reyes, Jose;Benitez, Javier
胃神经内分泌肿瘤（NETs）起源于肠嗜铬细胞样细胞，位于胃内的氧合腺内。I型肿瘤占胃NETs的70-80%，并与高胃血症、慢性萎缩性胃炎和胃酸过少有关。胃泌素参与胃酸产生的内分泌调节。大多数I型胃NETs是散发的，预后良好，其遗传基础尚不清楚。我们在一个有近亲父母和10个孩子的家庭中进行了外显子组测序研究，其中5个孩子患有I型胃NET。非典型临床特征包括发病年龄较早（约30岁）、侵袭性（3例有淋巴结浸润需要全胃切除术，1例为腺癌）和缺铁而非巨幼细胞贫血。我们在ATP4A基因的第14外显子（c.2107C > T）上发现了一个纯合错义突变，该突变编码负责胃壁细胞分泌酸的质子泵。氨基酸p.a g703cys在物种间高度保守，并引起一个跨膜结构域的改变，避免质子从细胞释放到胃。这与在受影响的个体中观察到的缺氯是一致的。散发性胃NET患者未发现ATP4A基因的种系或体细胞突变。基于这个大家族的结果，似乎这种非典型形式的胃NET发病年龄更早，表现更积极，具有与其他研究病例不同的非典型临床特征。
Gastric neuroendocrine tumours (NETs) arise from enterochromaffin-like cells, which are located in oxyntic glands within the stomach. Type I tumours represent 70-80% of gastric NETs and are associated with hypergastrinaemia, chronic atrophic gastritis and achlorhydria. Gastrin is involved in the endocrine regulation of gastric acid production. Most type I gastric NETs are sporadic, have a good prognosis and their genetic basis are unknown. We performed an exome sequencing study in a family with consanguineous parents and 10 children, five of whom were affected by type I gastric NET. Atypical clinical traits included an earlier age of onset (around 30 years), aggressiveness (three had nodal infiltration requiring total gastrectomy and one an adenocarcinoma) and iron-deficiency rather than megaloblastic anaemia. We identified a homozygous missense mutation in the 14th exon of the ATP4A gene (c.2107C > T), which encodes the proton pump responsible for acid secretion by gastric parietal cells. The amino acid p.Arg703Cys is highly conserved across species and originates a change of one of the transmembrane domains that avoids the liberation of protons from cells to stomach. This is consistent with the achlorhydria that was observed in the affected individuals. No germline or somatic mutations in the ATP4A gene were found in sporadic gastric NET patients. Based on the results of this large family, it seems that this atypical form of gastric NET has an earlier age of onset, behaves more aggressively and has atypical clinical traits that differentiated from other studied cases.