Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas
Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas
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CDH23（编码钙粘蛋白相关 23）的种系突变与家族性和散发性垂体腺瘤相关。
DOI：
10.1016/j.ajhg.2017.03.011
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发表时间：
2017-05-04
影响因子：
9.8
通讯作者：
Zhao, Yao
中科院分区：
文献类型：
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作者：
Zhang, Qilin;Peng, Cheng;Zhao, Yao
垂体腺瘤是颅内最常见的肿瘤之一。已经确定了PA的几个遗传易感因素，但它们只占病例的一小部分。在这项研究中，我们试图通过关注PA的致病突变来确定PA的遗传风险因素。在来自一个家族性PA的4名患病成员和17名无症状成员中，全外显子组测序鉴定了PA表型与钙粘蛋白相关23（CDH 23）中的杂合错义突变c.4136G>T（p.Arg1379Leu）的共分离。该突变导致CDH 23的细胞外钙粘蛋白（EC）结构域的钙结合基序中的氨基酸取代，并预测会损害细胞-细胞粘附。在总共12个家族性PA（20个个体）、125个散发性PA个体和260个对照个体中的基因组筛选显示，33%的家族性PA（4/12）和12%的散发性PA个体（15/125）具有功能性CDH 23变体。相比之下，0.8%的健康对照个体（2/260）携带功能性⑶ H 23变体。基于基因的分析还显示CDH 23基因型与PA之间存在显著关联（p = 5.54 3 10（-7））。此外，没有携带功能性CDH 23变体的PA个体显示肿瘤尺寸更大（p = 0.005）和更具侵袭性（p < 0.001）。因此，CDH 23基因突变与家族性和散发性PA有关，可能在PA的发病机制中起重要作用。
Pituitary adenoma (PA) is one of the most common intracranial neoplasms. Several genetic predisposing factors for PA have been identified, but they account for a small portion of cases. In this study, we sought to identify the PA genetic risk factors by focusing on causative mutations for PAs. Among the 4 affected and 17 asymptomatic members from one family with familial PA, whole-exome sequencing identified cosegregation of the PA phenotype with the heterozygous missense mutation c.4136G>T (p.Arg1379Leu) in cadherin-related 23 (CDH23). This mutation causes an amino acid substitution in the calcium-binding motif of the extracellular cadherin (EC) domains of CDH23 and is predicted to impair cell-cell adhesion. Genomic screening in a total of 12 families with familial PA (20 individuals), 125 individuals with sporadic PA, and 260 control individuals showed that 33% of the families with familial PA (4/12) and 12% of individuals with sporadic PA (15/125) harbored functional CDH23 variants. In contrast, 0.8% of the healthy control individuals (2/260) carried functional CDH23 variants. Gene-based analysis also revealed a significant association between CDH23 genotype and PA (p = 5.54 3 10(-7)). Moreover, PA individuals who did not harbor functional CDH23 variants displayed tumors that were larger in size (p = 0.005) and more invasive (p < 0.001). Therefore, mutations in CDH23 are linked with familial and sporadic PA and could play important roles in the pathogenesis of PA.