Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas

Qilin Zhang; Cheng Peng; Jianping Song; Yichao Zhang; Jianhua Chen; Zhijian Song; Xuefei Shou; Zengyi Ma; Hong Peng; Xuemin Jian; Wenqiang He; Zhao Ye; Zhiqiang Li; Yongfei Wang; Hongying Ye; Zhaoyun Zhang; Ming Shen; Feng Tang; Hong Chen; Zhifeng Shi; Chunjui Chen; Zhengyuan Chen; Yue Shen; Ye Wang; Shaoyong Lu; Jian Zhang; Yiming Li; Shiqi Li; Ying Mao; Liangfu Zhou; Hai Yan; Yongyong Shi; Chuanxin Huang; Yao Zhao

doi:10.1016/j.ajhg.2017.03.011

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. Epub 2017 Apr 13.

Authors

Qilin Zhang¹, Cheng Peng², Jianping Song¹, Yichao Zhang¹, Jianhua Chen³, Zhijian Song⁴, Xuefei Shou¹, Zengyi Ma¹, Hong Peng², Xuemin Jian⁴, Wenqiang He¹, Zhao Ye¹, Zhiqiang Li⁴, Yongfei Wang¹, Hongying Ye⁵, Zhaoyun Zhang⁵, Ming Shen¹, Feng Tang⁶, Hong Chen⁶, Zhifeng Shi¹, Chunjui Chen¹, Zhengyuan Chen¹, Yue Shen¹, Ye Wang¹, Shaoyong Lu⁷, Jian Zhang⁷, Yiming Li⁵, Shiqi Li¹, Ying Mao⁸, Liangfu Zhou¹, Hai Yan⁹, Yongyong Shi¹⁰, Chuanxin Huang¹¹, Yao Zhao¹²

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].

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.

MeSH terms

Amino Acid Sequence
Cadherin Related Proteins
Cadherins / genetics*
Case-Control Studies
Cell Adhesion
Genomics
Germ-Line Mutation*
Heterozygote
Humans
Pedigree
Phenotype
Pituitary Neoplasms / genetics*
Protein Conformation
Risk Factors

Substances

CDH23 protein, human
Cadherin Related Proteins
Cadherins