2. Academic Validation
  3. 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

  • Am J Hum Genet. 2017 May 4;100(5):817-823. doi: 10.1016/j.ajhg.2017.03.011.
Qilin Zhang 1,  Cheng Peng 2,  Jianping Song 1,  Yichao Zhang 1,  Jianhua Chen 3,  Zhijian Song 4,  Xuefei Shou 1,  Zengyi Ma 1,  Hong Peng 2,  Xuemin Jian 4,  Wenqiang He 1,  Zhao Ye 1,  Zhiqiang Li 4,  Yongfei Wang 1,  Hongying Ye 5,  Zhaoyun Zhang 5,  Ming Shen 1,  Feng Tang 6,  Hong Chen 6,  Zhifeng Shi 1,  Chunjui Chen 1,  Zhengyuan Chen 1,  Yue Shen 1,  Ye Wang 1,  Shaoyong Lu 7,  Jian Zhang 7,  Yiming Li 5,  Shiqi Li 1,  Ying Mao 8,  Liangfu Zhou 1,  Hai Yan 9,  Yongyong Shi 10,  Chuanxin Huang 11,  Yao Zhao 12
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; Shanghai Pituitary Tumor Center, Shanghai 200040, China.
  • 2 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.
  • 3 Bio-X Institutes, Ministry of Education Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Institute of Social Cognitive and Behavioral Sciences, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 4 Bio-X Institutes, Ministry of Education Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Institute of Social Cognitive and Behavioral Sciences, Shanghai Jiao Tong University, Shanghai 200030, China.
  • 5 Shanghai Pituitary Tumor Center, Shanghai 200040, China; Department of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
  • 6 Shanghai Pituitary Tumor Center, Shanghai 200040, China; Department of Pathology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
  • 7 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 8 Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; Shanghai Pituitary Tumor Center, Shanghai 200040, China; State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200040, China; Institute of Neurosurgery, Shanghai Medical College, Fudan University, Shanghai 200040, China.
  • 9 Department of Pathology, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA.
  • 10 Bio-X Institutes, Ministry of Education Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Institute of Social Cognitive and Behavioral Sciences, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Neuropsychiatric Science and Systems Biological Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Department of Psychiatry, First Teaching Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, China; Biomedical Sciences Institute of Qingdao University, Qingdao Branch of SJTU Bio-X Institutes and the Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China.
  • 11 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. Electronic address: [email protected].
  • 12 Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; Shanghai Pituitary Tumor Center, Shanghai 200040, China; State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200040, China; Institute of Neurosurgery, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: [email protected].
PMID: 28413019 DOI: 10.1016/j.ajhg.2017.03.011
Abstract

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 × 10-7). 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.

Keywords

CDH23; familial pituitary adenoma; mutation; pituitary adenoma; whole-exome sequencing.

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