• PMID: 25873734
• Gene Name: MCM8
• Condition: Primary gonadal failure
• Association: Associated
• Mutation: c.1954-1G>A, c.1469-1470insTA
• Population size: 2
• Population details: 2 families
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure

Tenenbaum-Rakover Y, Weinberg-Shukron A, Renbaum P, Lobel O, Eideh H, Gulsuner S, Dahary D, Abu-Rayyan A, Kanaan M, Levy-Lahad E, Bercovich D, Zangen D.

BACKGROUND: Primary gonadal failure is characterised by primary amenorrhoea or early menopause in females, and oligospermia or azoospermia in males. Variants of the minichromosome maintenance complex component 8 gene (MCM8) have recently been shown to be significantly associated with women's menopausal age in genome-wide association studies. Furthermore, MCM8-knockout mice are sterile. The objective of this study was to elucidate the genetic aetiology of gonadal failure in two consanguineous families presenting as primary amenorrhoea in the females and as small testes and azoospermia in a male. METHODS AND RESULTS: Using whole exome sequencing, we identified two novel homozygous mutations in the MCM8 gene: a splice (c.1954-1G>A) and a frameshift (c.1469-1470insTA). In each consanguineous family the mutation segregated with the disease and both mutations were absent in 100 ethnically matched controls. The splice mutation led to lack of the wild-type transcript and three different aberrant transcripts predicted to result in either truncated or significantly shorter proteins. Quantitative analysis of the aberrantly spliced transcripts showed a significant decrease in total MCM8 message in affected homozygotes for the mutation, and an intermediate decrease in heterozygous family members. Chromosomal breakage following exposure to mitomcyin C was significantly increased in cells from homozygous individuals for c.1954-1G>A, as well as c.1469-1470insTA. CONCLUSIONS: MCM8, a component of the pre-replication complex, is crucial for gonadal development and maintenance in humans-both males and females. These findings provide new insights into the genetic disorders of infertility and premature menopause in women. CI - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. FAU - Tenenbaum-Rakover, Yardena AU - Tenenbaum-Rakover Y AD - Pediatric Endocrine Unit, Ha'Emek Medical Center, Afula, Israel The Rappaport Faculty of Medicine, Technion, Haifa, Israel. FAU - Weinberg-Shukron, Ariella AU - Weinberg-Shukron A AD - Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel Hebrew University Medical School, Jerusalem, Israel. FAU - Renbaum, Paul AU - Renbaum P AD - Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel. FAU - Lobel, Orit AU - Lobel O AD - Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel Hebrew University Medical School, Jerusalem, Israel. FAU - Eideh, Hasan AU - Eideh H AD - Palestinian Medical Complex, Ramallah, USA. FAU - Gulsuner, Suleyman AU - Gulsuner S AD - Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington, USA. FAU - Dahary, Dvir AU - Dahary D AD - Toldot Genetics Ltd., Hod Hasharon, Israel. FAU - Abu-Rayyan, Amal AU - Abu-Rayyan A AD - Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine. FAU - Kanaan, Moien AU - Kanaan M AD - Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine. FAU - Levy-Lahad, Ephrat AU - Levy-Lahad E AD - Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel Hebrew University Medical School, Jerusalem, Israel. FAU - Bercovich, Dani AU - Bercovich D AD - Tel Hai College and GGA (Galilee Genetic Analysis lab), Tel Hai, Israel.