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
  • 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.