title: A non-sense MCM9 mutation in a familial case of primary ovarian insufficiency.
abstract: Primary ovarian insufficiency (POI) results in an early loss of ovarian function, and remains idiopathic in about 80% of cases. Here, we have performed a complete genetic study of a consanguineous family with two POI cases. Linkage analysis and homozygosity mapping identified 12 homozygous regions with linkage, totalling 84 Mb. Whole-exome sequencing of the two patients and a non-affected sister allowed us to detect a homozygous causal variant in the MCM9 gene. The variant c.1483G>T [p.E495*], confirmed using Sanger sequencing, introduced a premature stop codon in coding exon 8 and is expected to lead to the loss of a functional protein. MCM9 belongs to a complex required for DNA repair by homologous recombination, and its impairment in mouse is known to induce meiotic recombination defects and oocyte degeneration. A previous study recently described two consanguineous families in which homozygous mutations of MCM9 were responsible for POI and short stature. Interestingly, the affected sisters in the family described here had a normal height. Altogether, our results provide the confirmation of the implication of MCM9 variants in POI and expand their phenotypic spectrum.
authors.affiliation: Institut Jacques Monod, Paris, France.|Department of Biology, Université Paris Diderot-Paris VII, Paris Cedex, France.
authors.forename: F
authors.initials: F
authors.lastname: Fauchereau
authors.affiliation: Department of Obstetrics and Gynecology, The Rappaport Faculty of Medicine, Haifa, Israel.|Genetic Institute, Haemek Medical Center, Afula, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Shalev
authors.affiliation: Department of Obstetrics and Gynecology, The Rappaport Faculty of Medicine, Haifa, Israel.|Genetic Institute, Haemek Medical Center, Afula, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Chervinsky
authors.affiliation: OBGYN Department, Emek Medical Center, Afula, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Beck-Fruchter
authors.affiliation: Institut Jacques Monod, Paris, France.|Department of Biology, Université Paris Diderot-Paris VII, Paris Cedex, France.
authors.forename: B
authors.initials: B
authors.lastname: Legois
authors.affiliation: Department of Genetics and Development, Institut Cochin, Paris, France.|Faculty of Medicine, Université Paris Descartes-Paris V, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Fellous
authors.affiliation: Institut Jacques Monod, Paris, France.|Department of Biology, Université Paris Diderot-Paris VII, Paris Cedex, France.
authors.forename: S
authors.initials: S
authors.lastname: Caburet
authors.affiliation: Institut Jacques Monod, Paris, France.|Department of Biology, Université Paris Diderot-Paris VII, Paris Cedex, France.
authors.forename: R A
authors.initials: RA
authors.lastname: Veitia
mesh_terms: D001483:Base Sequence; D018389:Codon, Nonsense; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D064110:Minichromosome Maintenance Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D016649:Primary Ovarian Insufficiency / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C501931:MCM9 protein, human; D064110:Minichromosome Maintenance Proteins
keywords: MCM9; exome sequencing; infertility; primary ovarian insufficiency; reproductive medicine