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Compound heterozygous DMC1 variants cause non-obstructive azoospermia by defective replication protein A replacement
Yan Wang1, Renxue Wang1, Ziyou Bao1
1State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, 250012, China.; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China.; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China.; Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China.; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China.; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention (Under Construction), Jinan, Shandong, 250012, China.; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China.
Research Question:
How does a compound heterozygous DMC1 variant, a meiosis-specific recombinase, affect homologous search and chain invasion during spermatocyte meiosis in a patient with non-obstructive azoospermia (NOA)?
Design:
A patient with a compound heterozygous DMC1 variant associated with NOA was identified. Reverse transcription polymerase chain reaction and western blot were used to study the effect of this variant. Standard histological analysis and immunofluorescence staining investigated the patient's spermatogenic arrest. The accumulation of replication protein A (RPA), a single-stranded DNA-binding protein, was detected through immunofluorescence staining on chromosome spreads of spermatocytes. Dmc1 knockout (Dmc1-/-) mice were constructed to replicate the results of chromosome spreads observed in the patient.
Results:
The patient's compound heterozygous DMC1 variants (c.494+4A>G/c.597G>C) were associated with NOA. This patient showed nonsense-mediated mRNA decay of DMC1, significantly reducing DMC1 protein levels in germ cells. Spermatogenic arrest occurred during meiosis, with defects in chromosome pairing and DNA double-strand break repair. Dmc1-/- mice precisely replicated the human phenotype of defects in chromosome pairing and double-strand break repair. Further analysis revealed that, in the absence of DMC1, RPA (single-stranded DNA-binding protein) failed to be replaced by meiosis recombinase, leading to an accumulation in zygotene stage spermatocytes. This was confirmed by the Dmc1 knockout mouse model.
Conclusions:
This novel compound heterozygous DMC1 variant disrupts germ cell meiosis and expands the known mutational spectrum of DMC1.
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