title: Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure.
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.
  
  
  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.
authors: Pediatric Endocrine Unit, Ha'Emek Medical Center, Afula, Israel The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Yardena
authors: Y
authors: Tenenbaum-Rakover
authors: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel Hebrew University Medical School, Jerusalem, Israel.
authors: Ariella
authors: A
authors: Weinberg-Shukron
authors: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors: Paul
authors: P
authors: Renbaum
authors: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel Hebrew University Medical School, Jerusalem, Israel.
authors: Orit
authors: O
authors: Lobel
authors: Palestinian Medical Complex, Ramallah, USA.
authors: Hasan
authors: H
authors: Eideh
authors: Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington, USA.
authors: Suleyman
authors: S
authors: Gulsuner
authors: Toldot Genetics Ltd., Hod Hasharon, Israel.
authors: Dvir
authors: D
authors: Dahary
authors: Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.
authors: Amal
authors: A
authors: Abu-Rayyan
authors: Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.
authors: Moien
authors: M
authors: Kanaan
authors: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel Hebrew University Medical School, Jerusalem, Israel.
authors: Ephrat
authors: E
authors: Levy-Lahad
authors: Tel Hai College and GGA (Galilee Genetic Analysis lab), Tel Hai, Israel.
authors: Dani
authors: D
authors: Bercovich
authors: Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: David
authors: D
authors: Zangen
mesh_terms: D000293:Adolescent; D000483:Alleles; D043171:Chromosomal Instability; D019457:Chromosome Breakage; D002874:Chromosome Mapping; D003241:Consanguinity; D056915:DNA Copy Number Variations; D018076:DNA, Complementary / Q000235:genetics; D059472:Exome; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006058:Gonadal Disorders / Q000175:diagnosis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D064187:Minichromosome Maintenance Complex Component 8 / Q000235:genetics*; D009154:Mutation; D010053:Ovary / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites; D012333:RNA, Messenger / Q000235:genetics; D035781:Siblings
chemical_list: D018076:DNA, Complementary; D022821:RNA Splice Sites; D012333:RNA, Messenger; D064187:Minichromosome Maintenance Complex Component 8
keywords: Chromosomal; Clinical genetics; Endocrinology; Genetics