Novel Variants in MDC1 are Associated With Severe Oligoasthenoteratozoospermia

Area of Science:

• Genetics
• Molecular Biology
• Reproductive Medicine

Background:

• Mediator of DNA damage checkpoint 1 (MDC1) is crucial for DNA damage repair.
• Severe oligoasthenoteratozoospermia (OAT) is a complex male infertility condition.
• Genetic factors are increasingly recognized in OAT etiology.

Purpose of the Study:

• To identify novel genetic variants in MDC1 associated with severe OAT.
• To investigate the functional consequences of identified MDC1 variants.
• To explore the potential of MDC1 variants for genetic diagnosis in OAT.

Main Methods:

• Genetic sequencing to identify MDC1 variants in OAT patients.
• In vitro experiments to assess protein truncation and degradation.
• Immunofluorescence assays to evaluate MDC1 and γH2AX colocalization.

Main Results:

• Three novel MDC1 variants (p.R1993X, p.R1882X, and p.M1L) were identified in two OAT patients.
• p.R1882X and p.R1993X variants led to MDC1 protein truncation and subsequent degradation.
• MDC1 variants disrupted the colocalization of MDC1 with γH2AX, impacting DNA damage response.

Conclusions:

• This study reports the first screening of MDC1 variants in OAT patients.
• Identified MDC1 variants provide a basis for precise genetic diagnosis in OAT.
• The findings expand the known spectrum of MDC1 variants and inform targeted therapeutic strategies for OAT.