Zhang Qilin, Peng Cheng, Song Jianping, Zhang Yichao, Chen Jianhua, Song Zhijian, Shou Xuefei, Ma Zengyi, Peng Hong, Jian Xuemin, He Wenqiang, Ye Zhao, Li Zhiqiang, Wang Yongfei, Ye Hongying, Zhang Zhaoyun, Shen Ming, Tang Feng, Chen Hong, Shi Zhifeng, Chen Chunjui, Chen Zhengyuan, Shen Yue, Wang Ye, Lu Shaoyong, Zhang Jian, Li Yiming, Li Shiqi, Mao Ying, Zhou Liangfu, Yan Hai, Shi Yongyong, Huang Chuanxin, Zhao Yao
Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; Shanghai Pituitary Tumor Center, Shanghai 200040, China.
Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Am J Hum Genet. 2017 May 4;100(5):817-823. doi: 10.1016/j.ajhg.2017.03.011. Epub 2017 Apr 13.
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 × 10). 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.
垂体腺瘤（PA）是最常见的颅内肿瘤之一。已经确定了几种PA的遗传易感因素，但它们仅占病例的一小部分。在本研究中，我们试图通过关注PA的致病突变来确定PA的遗传危险因素。在一个患有家族性PA的家族中，4名患者和17名无症状成员中，全外显子测序确定PA表型与钙黏蛋白相关23（CDH23）中的杂合错义突变c.4136G>T（p.Arg1379Leu）共分离。该突变导致CDH23细胞外钙黏蛋白（EC）结构域的钙结合基序中的氨基酸替换，并预计会损害细胞间黏附。对总共12个患有家族性PA的家族（20人）、125名散发性PA患者和260名对照个体进行的基因组筛查显示，33%的家族性PA家族（4/12）和12%的散发性PA个体（15/125）携带功能性CDH23变体。相比之下，0.8%的健康对照个体（2/260）携带功能性CDH23变体。基于基因的分析还揭示了CDH23基因型与PA之间存在显著关联（p = 5.54 × 10）。此外，未携带功能性CDH23变体的PA个体表现出肿瘤更大（p = 0.005）且侵袭性更强（p < 0.001）。因此，CDH23突变与家族性和散发性PA相关，并可能在PA的发病机制中起重要作用。
