title: MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability.
abstract: Premature ovarian failure (POF) is genetically heterogeneous and manifests as hypergonadotropic hypogonadism either as part of a syndrome or in isolation. We studied two unrelated consanguineous families with daughters exhibiting primary amenorrhea, short stature, and a 46,XX karyotype. A combination of SNP arrays, comparative genomic hybridization arrays, and whole-exome sequencing analyses identified homozygous pathogenic variants in MCM9, a gene implicated in homologous recombination and repair of double-stranded DNA breaks. In one family, the MCM9 c.1732+2T>C variant alters a splice donor site, resulting in abnormal alternative splicing and truncated forms of MCM9 that are unable to be recruited to sites of DNA damage. In the second family, MCM9 c.394C>T (p.Arg132(∗)) results in a predicted loss of functional MCM9. Repair of chromosome breaks was impaired in lymphocytes from affected, but not unaffected, females in both families, consistent with MCM9 function in homologous recombination. Autosomal-recessive variants in MCM9 cause a genomic-instability syndrome associated with hypergonadotropic hypogonadism and short stature. Preferential sensitivity of germline meiosis to MCM9 functional deficiency and compromised DNA repair in the somatic component most likely account for the ovarian failure and short stature.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Wood-Trageser
authors.affiliation: Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, Adana 01330, Turkey.
authors.forename: Fatih
authors.initials: F
authors.lastname: Gurbuz
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Yatsenko
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Jeffries
authors.affiliation: Department of Biotechnology, Institute of Sciences, Cukurova University, Adana 01330, Turkey.
authors.forename: L Damla
authors.initials: LD
authors.lastname: Kotan
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Urvashi
authors.initials: U
authors.lastname: Surti
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Ketterer
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Jelena
authors.initials: J
authors.lastname: Matic
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Chipkin
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Huaiyang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Trakselis
authors.affiliation: Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, Adana 01330, Turkey.
authors.forename: A Kemal
authors.initials: AK
authors.lastname: Topaloglu
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Human Genetics, University of Pittsburgh, PA 15261, USA. Electronic address: rajkovic@upmc.edu.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rajkovic
mesh_terms: D059786:Abnormal Karyotype; D000293:Adolescent; D000328:Adult; D000568:Amenorrhea / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D043171:Chromosomal Instability / Q000235:genetics*; D003241:Consanguinity; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004392:Dwarfism / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D059765:Homologous Recombination; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D064110:Minichromosome Maintenance Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D022821:RNA Splice Sites; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D022821:RNA Splice Sites; C501931:MCM9 protein, human; D064110:Minichromosome Maintenance Proteins