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

Carolina Carlosama, Maëva El Zaiat, Liliana C Patiño, Heidi E Mateus, Reiner A Veitia, Paul Laissue

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 incriminated as being responsible for this condition.

Original languageEnglish (US)
JournalHuman Molecular Genetics
Volume26
Issue number16
DOIs
StatePublished - Aug 15 2017

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Primary Ovarian Insufficiency
RNA Splice Sites
Mutation
Genes
Exons
Exome
Menstruation
DNA Repair
Infertility
Adenosine Triphosphate
Pathology
Proteins

Cite this

Carlosama, Carolina ; El Zaiat, Maëva ; Patiño, Liliana C ; Mateus, Heidi E ; Veitia, Reiner A ; Laissue, Paul. / A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 16.
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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 incriminated as being responsible for this condition.",
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A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency. / Carlosama, Carolina; El Zaiat, Maëva; Patiño, Liliana C; Mateus, Heidi E; Veitia, Reiner A; Laissue, Paul.

In: Human Molecular Genetics, Vol. 26, No. 16, 15.08.2017.

Research output: Contribution to journalArticle

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T1 - A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency

AU - Carlosama, Carolina

AU - El Zaiat, Maëva

AU - Patiño, Liliana C

AU - Mateus, Heidi E

AU - Veitia, Reiner A

AU - Laissue, Paul

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PY - 2017/8/15

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AB - 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 incriminated as being responsible for this condition.

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