Novel Variants in <scp> <i>MDC1</i> </scp> are Associated With Severe Oligoasthenoteratozoospermia

Mediator of DNA damage checkpoint 1 (MDC1) is a protein closely associated with the repair of DNA damage. Recently, we identified three novel variants (NM_014641.3:c.C5977T; p.R1993X) (NM_014641.3:c.C5644T; p.R1882X; c.A1T; p.M1L) in MDC1 in two patients with severe oligoasthenoteratozoospermia (OAT). In vitro validation showed that the p.R1882X variant resulted in the truncation of the MDC1 protein, and the p.R1993X variant resulted in the degradation of the MDC1 protein after truncation. Immunofluorescence demonstrated that the truncated protein caused by the variants affected the colocalization relationship between MDC1 and its interacting protein γH2AX. Additionally, one of the patients and his wife underwent intracytoplasmic sperm injection (ICSI), but the result was unsatisfactory. We screened out the variants of MDC1 in patients with OAT for the first time, and this research could afford precise genetic diagnosis for the patients. It has broadened the variant spectrum of MDC1 , which is conducive to the development of targeted therapeutic strategies.