title: Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability.
abstract: Premature ovarian failure (POF) is a genetically and phenotypically heterogeneous disorder that includes individuals with manifestations ranging from primary amenorrhea to loss of menstrual function prior to age 40. POF presents as hypergonadotropic hypogonadism and can be part of a syndrome or occur in isolation. Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism. The sisters were born to parents who are first cousins. SNP analysis and whole-exome sequencing revealed the presence of a pathogenic variant of the minichromosome maintenance 8 gene (MCM8, c.446C>G; p.P149R) located within a region of homozygosity that was present in the affected daughters but not in their unaffected sisters. Because MCM8 participates in homologous recombination and dsDNA break repair, we tested fibroblasts from the affected sisters for hypersensitivity to chromosomal breaks. Compared with fibroblasts from unaffected daughters, chromosomal break repair was deficient in fibroblasts from the affected individuals, likely due to inhibited recruitment of MCM8 p.P149R to sites of DNA damage. Our study identifies an autosomal recessive disorder caused by an MCM8 mutation that manifests with endocrine dysfunction and genomic instability.
authors.forename: Saleh
authors.initials: S
authors.lastname: AlAsiri
authors.forename: Sulman
authors.initials: S
authors.lastname: Basit
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Wood-Trageser
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Yatsenko
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Jeffries
authors.forename: Urvashi
authors.initials: U
authors.lastname: Surti
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Ketterer
authors.forename: Sibtain
authors.initials: S
authors.lastname: Afzal
authors.forename: Khushnooda
authors.initials: K
authors.lastname: Ramzan
authors.forename: Muhammad
authors.initials: M
authors.lastname: Faiyaz-Ul Haque
authors.forename: Huaiyang
authors.initials: H
authors.lastname: Jiang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Trakselis
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rajkovic
mesh_terms: D043171:Chromosomal Instability; D003241:Consanguinity; D004260:DNA Repair; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008126:Lod Score; D008875:Middle Aged; D064110:Minichromosome Maintenance Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D011485:Protein Binding
chemical_list: C471623:MCM8 protein, human; D064110:Minichromosome Maintenance Proteins