Minichromosome maintenance complex component 8 mutations cause primary ovarian insufficiency

Area of Science:

• Genetics and genomics
• Reproductive biology
• Molecular and cell biology

Background:

• Primary ovarian insufficiency (POI) affects women of reproductive age.
• The genetic basis of sporadic POI is not fully understood.
• Minichromosome maintenance complex component 8 (MCM8) is involved in DNA replication and repair.

Purpose of the Study:

• To investigate MCM8 gene mutations in patients with sporadic POI.
• To assess the functional impact of identified MCM8 variants on DNA repair.

Main Methods:

• Retrospective case-control study involving 192 POI patients and 312 controls.
• Sanger sequencing of the MCM8 gene.
• Functional assays using mitomycin C (MMC) to evaluate DNA repair capacity via histone H2AX phosphorylation.

Main Results:

• Two novel missense variants (p. H317L and p. H601R) in MCM8 were identified in two POI patients and absent in controls.
• Cells expressing mutant MCM8 showed increased sensitivity to MMC.
• Mutant p. H317L exhibited impaired DNA repair capacity.

Conclusions:

• Novel MCM8 mutations p. H317L and p. H601R are potentially causative for POI.
• Dysfunctional DNA repair due to MCM8 mutations may underlie POI pathogenesis.