Abstract
BACKGROUND: Minichromosome maintenance complex component 8 (MCM8) is responsible for homologous recombination and DNA double-strand breaks (DSBs) repair and is the cause of primary ovarian insufficiency (POI), which is seldom diagnosed in adolescents and children. METHODS: Whole-exome sequencing was performed in a 13-year-old girl, and Sanger sequencing was used to identify potentially pathogenic variants in her sister (aged 6 years and 7 months) and parents. To identify potential pathogenic mutations, DSBs were induced by mitomycin C (MMC), and the DNA repair capacity was evaluated by the histone H2AX phosphorylation level. RESULTS: Two novel mutations of MCM8, i.e., c.724T>C (p.C242R) and c.1334C>A (p.S445*), were identified in a 13-year-old girl with POI who exhibited disappeared bilateral ovaries and short stature (height standard difference score [HtSDS] = -3.05), and her sister (aged 6 years and 7 months) with progressive POI whose ovary size decreased from normal to unclear and height growth gradually slowed. In the functional experiments, compared with the wild-type, HeLa cells overexpressing mutant p.C242R and p.S445* showed a higher sensitivity to MMC. Furthermore, the mutant p.S445* has a more deleterious effect on DNA damage repair. CONCLUSION: Our results reveal that affected children with the novel pathogenetic mutations p.C242R and p.S445* in the MCM8 gene are characterized by POI, short stature, cancer susceptibility, and genomic instability.