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A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency
- Source :
- Repositorio EdocUR-U. Rosario, Universidad del Rosario, instacron:Universidad del Rosario
- Publication Year :
- 2017
- Publisher :
- Oxford University Press, 2017.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Luteinizing hormone
Sanger sequencing
Unclassified drug
Karyotype 46
Uterus myoma
Menopause, Premature
Thyrotropin
Cell Cycle Proteins
Gene mutation
Gene sequence
Primary Ovarian Insufficiency
XX
Gene
Thyrotropin blood level
MSH4 protein
Whole Exome Sequencing
Cohort Studies
Exon
0302 clinical medicine
Genetics (clinical)
Exome sequencing
Priority journal
Genetics
030219 obstetrics & reproductive medicine
Heterozygosity
Inheritance
Messenger RNA
Homozygote
General Medicine
Exons
Complementary DNA
Premature ovarian failure
Pedigree
Early menopause
Chemistry
Hela cell line
Reverse transcription polymerase chain reaction
Female
Cohort analysis
Menopause
Luteinizing hormone blood level
Exon skipping
Human
Adult
MSH4 gene
Heterozygote
Biology
Premature ovarian insufficiency
Secondary amenorrhea
Article
03 medical and health sciences
Exon trapping
Exome Sequencing
Case report
medicine
Humans
Genetic variation
Segregation analysis
Molecular Biology
Premature
Transvaginal echography
RNA splice site
Follitropin blood level
Menarche
DNA fragment
Protein
Follitropin
medicine.disease
Gene frequency
030104 developmental biology
MSH4
Menstrual irregularity
Metabolism
Human cell
Mutation
RNA Splice Sites
Controlled study
Cell cycle protein
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Repositorio EdocUR-U. Rosario, Universidad del Rosario, instacron:Universidad del Rosario
- Accession number :
- edsair.doi.dedup.....1371cb15cee955299660fc1028aa67cb