Year: 2022
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Hypospadias is a congenital anomaly of the male urogenital system. Genetics factors play an important role in its pathogenesis. To search for potential causal genes/variants for hypospadias, we performed exome sequencing in a pedigree with three patients across two generations and a cohort of 49 sporadic patients with hypospadias. RESULTS: A novel BRAF variant (NM_004333.6: c.362C > A) was found to co-segregate with the hypospadias phenotype in the disease pedigree. In cells overexpressing the BRAF mutant, the phosphorylation level of p38 MAPK was significantly increased as compared with the cells overexpressing the wild-type BRAF or RASopathy-related BRAF mutant. This variant further led to a reduced transcription level of the SRY gene, which is essential for the normal development of the male reproductive system. In the cohort of sporadic patients, we identified two additional variants in p38 MAPK signaling-related genes (TRIM67 and DAB2IP) potentially associated with hypospadias. CONCLUSION: Our study expands the phenotypic spectrum of variants affecting p38 MAPK signaling toward the involvement of hypospadias.
Authors: Defu Lin, Huakang Du, Sen Zhao, Bowen Liu, Hongcheng Song, Guannan Wang, Weiping Zhang, Haiyan Liang, Pei Liu, Chao Liu, Wenwen Han, Zhenwu Li, Yang Yang, Shuofan Chen, Lina Zhao, Xiaoxin Li, Zhihong Wu, DISCO (Deciphering Disorders Involving Scoliosis & COmorbidities) study group, Guixing Qiu, Zhihong Wu, Terry Jianguo Zhang, Nan Wu, Shengru Wang, Jiaqi Liu, Sen Liu, Yuzhi Zuo, Gang Liu, Chenxi Yu, Lian Liu, Jiashen Shao, Sen Zhao, Zihui Yan, Hengqiang Zhao, Yuchen Niu, Xiaoxin Li, Huizi Wang, Congcong Ma, Zefu Chen, Bowen Liu, Xi Cheng, Jiachen Lin, Huakang Du, Yaqi Li, Shuang Song, Weijie Tian, Zhixin Xie, Zhengye Zhao, Lina Zhao, Zhi Zhao, Zhifa Zheng, Yingzhao Huang, Ning Sun, Nan Wu
Language: English
Subfield: Urology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,680
Funders: Innovative Research Group Project of the National Natural Science Foundation of China, National Natural Science Foundation of China, Tsinghua University, Natural Science Foundation of Beijing Municipality, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Peking Union Medical College, National Key Research and Development Program of China
OpenAlex ID: W4281289186