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Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure
  1. Yardena Tenenbaum-Rakover1,2,
  2. Ariella Weinberg-Shukron3,4,
  3. Paul Renbaum3,
  4. Orit Lobel3,4,
  5. Hasan Eideh5,
  6. Suleyman Gulsuner6,
  7. Dvir Dahary7,
  8. Amal Abu-Rayyan8,
  9. Moien Kanaan8,
  10. Ephrat Levy-Lahad3,4,
  11. Dani Bercovich9,
  12. David Zangen10
  1. 1Pediatric Endocrine Unit, Ha'Emek Medical Center, Afula, Israel
  2. 2The Rappaport Faculty of Medicine, Technion, Haifa, Israel
  3. 3Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel
  4. 4Hebrew University Medical School, Jerusalem, Israel
  5. 5Palestinian Medical Complex, Ramallah, USA
  6. 6Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington, USA
  7. 7Toldot Genetics Ltd., Hod Hasharon, Israel
  8. 8Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine
  9. 9Tel Hai College and GGA (Galilee Genetic Analysis lab), Tel Hai, Israel
  10. 10Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
  1. Correspondence to Dr Yardena Tenenbaum-Rakover, Pediatric Endocrine Unit, Ha'Emek Medical Center, Afula 18101, Israel; rakover_y{at}clalit.org.il

Abstract

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.

  • Chromosomal
  • Clinical genetics
  • Endocrinology
  • Genetics

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