• PMID: 29331980
• Gene Name: DMC1
• Condition: Non-obstructive azoospermia
• Association: Associated
• Mutation: c.106G>A, p.Asp36Asn
• Population size: 2
• Population details: 2
• Sex: Male, Female
• Infertility type: Male infertility
• Associated genes: NGS
• Other associated phenotypes: Premature ovarian insufficiency (POI)

DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing

He WB, Tu CF, Liu Q, Meng LL, Yuan SM, Luo AX, He FS, Shen J, Li W, Du J, Zhong CG, Lu GX, Lin G, Fan LQ, Tan YQ.

BACKGROUND: The genetic causes of the majority of male and female infertility caused by human non-obstructive azoospermia (NOA) and premature ovarian insufficiency (POI) with meiotic arrest are unknown. OBJECTIVE: To identify the genetic cause of NOA and POI in two affected members from a consanguineous Chinese family. METHODS: We performed whole-exome sequencing of DNA from both affected patients. The identified candidate causative gene was further verified by Sanger sequencing for pedigree analysis in this family. In silico analysis was performed to functionally characterise the mutation, and histological analysis was performed using the biopsied testicle sample from the male patient with NOA. RESULTS: We identified a novel homozygous missense mutation (NM_007068.3: c.106G>A, p.Asp36Asn) in DMC1, which cosegregated with NOA and POI phenotypes in this family. The identified missense mutation resulted in the substitution of a conserved aspartic residue with asparaginate in the modified H3TH motif of DMC1. This substitution results in protein misfolding. Histological analysis demonstrated a lack of spermatozoa in the male patient's seminiferous tubules. Immunohistochemistry using a testis biopsy sample from the male patient showed that spermatogenesis was blocked at the zygotene stage during meiotic prophase I. CONCLUSIONS: To the best of our knowledge, this is the first report identifying DMC1 as the causative gene for human NOA and POI. Furthermore, our pedigree analysis shows an autosomal recessive mode of inheritance for NOA and POI caused by DMC1 in this family. CI - © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. FAU - He, Wen-Bin AU - He WB AD - Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Tu, Chao-Feng AU - Tu CF AD - Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Liu, Qiang AU - Liu Q AD - Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China. AD - Hunan Cancer Hospital and The Affiliated Cancer of Xiangya School of Medicine, Central South University, Changsha, China. FAU - Meng, Lan-Lan AU - Meng LL AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. FAU - Yuan, Shi-Min AU - Yuan SM AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. FAU - Luo, Ai-Xiang AU - Luo AX AD - Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - He, Fu-Sheng AU - He FS AD - BGI Genomics, BGI-Shenzhen, Shenzhen, China. FAU - Shen, Juan AU - Shen J AD - BGI Genomics, BGI-Shenzhen, Shenzhen, China. FAU - Li, Wen AU - Li W AD - Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Du, Juan AU - Du J AD - Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Zhong, Chang-Gao AU - Zhong CG AD - Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Lu, Guang-Xiu AU - Lu GX AD - Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Lin, Ge AU - Lin G AD - Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Fan, Li-Qing AU - Fan LQ AD - Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China.