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.
- non-obstructive azoospermia
- premature ovarian insufficiency
- whole-exome sequencing
- dmc 1 gene
- meiotic arrest
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W-BH and C-FT contributed equally.
Contributors Contributors Y-QT designed the research; W-BH, C-FT performed the research; L-LM, S-MY, A-XL, F-SH, JS, JD and WL performed the bioinformatics analysis; L-QF, GL and G-XL analysed the data; Y-QT, W-BH and C-FT analysed the data and wrote the paper.
Funding This study was supported by grants from the National Natural Science Foundation of China (81771645 and 81471432 to Y-QT), the National Key Research and Development Program of China (2016YFC1000600 to L-QF) and Graduate Research and Innovation Projects of Central South University (grant 2017zzts071).
Competing interests None declared.
Patient consent Obtained.
Ethics approval This study was approved by the institutional ethics committees of the Reproductive and Genetic Hospital of CITIC Xiangya and Central South University. Written informed consent was obtained from all participating individuals.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The manuscript presents a mutation in a gene not previously associated with both NOA in males and POI in females in a family. No additional unpublished data are available from the study.
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