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Minichromosome maintenance complex component 8 mutations cause primary ovarian insufficiency
- Source :
- Fertility and Sterility. 106:1485-1489.e2
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- Objective To investigate whether mutations in the minichromosome maintenance complex component 8 (MCM8) gene were present in 192 patients with sporadic primary ovarian insufficiency (POI). Design Retrospective case-control cohort study. Setting University-based reproductive medicine center. Patient(s) A total of 192 patients with sporadic POI and 312 control women with regular menstruation (192 age-matched women and 120 women >45 years old). Intervention(s) Sanger sequencing was performed in patients with sporadic POI, and potentially pathogenic variants were confirmed in matched controls. DNA damage was induced by mitomycinC (MMC) treatment, and DNA repair capacity was evaluated by histone H2AX phosphorylation level. Main Outcome Measure(s) Sanger sequencing for MCM8 was performed in 192 patients with sporadic POI, and functional experiments were performed to explore the deleterious effects of mutations identified. Result(s) Two novel missense variants in MCM8 , c. A950T (p. H317L), and c. A1802G (p. H601R), were identified in two patients with POI but absent in 312 controls (the upper 90% confidence limit for the proportion 2/192 is 2.24%). The HeLa cells overexpressing mutant p. H317L and p. H601R showed higher sensitivity to MMC compared with wild type. Furthermore, mutant p. H317L showed decreased repair capacity after MMC treatment with much more histone H2AX phosphorylation remaining after 2 hours of recovery. Conclusion(s) Our result suggests novel mutations p. H317L and p. H601R in the MCM8 gene are potentially causative for POI by dysfunctional DNA repair.
- Subjects :
- Adult
0301 basic medicine
Time Factors
Adolescent
DNA Repair
DNA repair
DNA damage
DNA Mutational Analysis
Mutant
Mutation, Missense
Primary Ovarian Insufficiency
Biology
Transfection
Bioinformatics
Histones
Young Adult
03 medical and health sciences
symbols.namesake
Minichromosome maintenance
Risk Factors
Humans
Missense mutation
Genetic Predisposition to Disease
Phosphorylation
Gene
Genetic Association Studies
Retrospective Studies
Sanger sequencing
Academic Medical Centers
Minichromosome Maintenance Proteins
Wild type
Obstetrics and Gynecology
Phenotype
030104 developmental biology
Reproductive Medicine
symbols
Female
DNA Damage
HeLa Cells
Subjects
Details
- ISSN :
- 00150282
- Volume :
- 106
- Database :
- OpenAIRE
- Journal :
- Fertility and Sterility
- Accession number :
- edsair.doi.dedup.....a84ad838b6d44fac8deb6b70a0dd32a4