RT Journal Article
SR Electronic
T1 Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 391
OP 399
DO 10.1136/jmedgenet-2014-102921
VO 52
IS 6
A1 Yardena Tenenbaum-Rakover
A1 Ariella Weinberg-Shukron
A1 Paul Renbaum
A1 Orit Lobel
A1 Hasan Eideh
A1 Suleyman Gulsuner
A1 Dvir Dahary
A1 Amal Abu-Rayyan
A1 Moien Kanaan
A1 Ephrat Levy-Lahad
A1 Dani Bercovich
A1 David Zangen
YR 2015
UL http://jmg.bmj.com/content/52/6/391.abstract
AB 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.