A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency

Premature ovarian insufficiency (POI) is a frequent pathology that affects women under 40 years of age, characterized by an early cessation of menses and high FSH levels. Despite recent progresses in molecular diagnosis, the etiology of POI remains idiopathic in most cases. Whole-exome sequencing of members of a Colombian family affected by POI allowed us to identify a novel homozygous donor splice-site mutation in the meiotic gene MSH4 (MutS Homolog 4). The variant followed a strict mendelian segregation within the family and was absent in a cohort of 135 women over 50 years of age without history of infertility, from the same geographical region as the affected family. Exon trapping experiments showed that the splice-site mutation induced skipping of exon 17. At the protein level, the mutation p.Ile743_Lys785del is predicted to lead to the ablation of the highly conserved Walker B motif of the ATP-binding domain, thus inactivating MSH4. Our study describes the first MSH4 mutation associated with POI and increases the number of meiotic/DNA repair genes formally implicated as being responsible for this condition. © The Author 2017. Published by Oxford University Press. All rights reserved.

• Fecha de publicación: 2017
• Institución: Universidad del Rosario
• Repositorio: Repositorio EdocUR - U. Rosario
• Idioma: eng
• OAI Identifier: oai:repository.urosario.edu.co:10336/24224
• Acceso en línea: https://doi.org/10.1093/hmg/ddx199; https://repository.urosario.edu.co/handle/10336/24224
• Palabra clave: Complementary DNA; DNA fragment; Follitropin; Luteinizing hormone; Messenger RNA; MSH4 protein; Protein; Thyrotropin; Unclassified drug; Cell cycle protein; Adult; Article; Case report; Cohort analysis; Controlled study; Exon skipping; Female; Follitropin blood level; Gene; Gene frequency; Gene mutation; Gene sequence; Genetic variation; Hela cell line; Heterozygosity; Heterozygote; Human; Human cell; Inheritance; Luteinizing hormone blood level; Menarche; Menstrual irregularity; MSH4 gene; Pedigree; Premature ovarian failure; Priority journal; Reverse transcription polymerase chain reaction; Sanger sequencing; Secondary amenorrhea; Segregation analysis; Thyrotropin blood level; Transvaginal echography; Uterus myoma; Chemistry; Early menopause; Exon; Genetics; Homozygote; Metabolism; Mutation; Premature ovarian failure; RNA splice site; Whole exome sequencing; Adult; Cell Cycle Proteins; Cohort Studies; Exons; Female; Homozygote; Humans; Mutation; Pedigree; Primary Ovarian Insufficiency; RNA Splice Sites; Whole Exome Sequencing; human; XX; Premature; MSH4 protein; Karyotype 46; Menopause
• License: Abierto (Texto Completo)