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

doi:10.1093/hmg/ddx199

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

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

63 Citas (Scopus)

Resumen

La insuficiencia ovárica prematura (IOP) es una patología frecuente que afecta a las mujeres menores de 40 años de edad, caracterizada por un cese temprano de la menstruación y altos niveles de FSH. A pesar de los recientes avances en el diagnóstico molecular, la etiología de los PDI sigue siendo idiopática en la mayoría de los casos. La secuenciación del exoma completo de los miembros de una familia colombiana afectada por el PDI nos permitió identificar una nueva mutación homocigótica en el sitio de empalme del gen meiótico MSH4 (MutS Homolog 4). La variante siguió una estricta segregación mendeliana dentro de la familia y estuvo ausente en una cohorte de 135 mujeres mayores de 50 años sin antecedentes de infertilidad, de la misma región geográfica que la familia afectada. Los experimentos de captura de exón mostraron que la mutación en el sitio de empalme indujo la omisión del exón 17. A nivel proteico, se predice que la mutación p.Ile743_Lys785del conducirá a la ablación del motivo Walker B altamente conservado del dominio de unión ATP, desactivando así el MSH4. Nuestro estudio describe la primera mutación MSH4 asociada con POI y aumenta el número de genes meióticos/de reparación de ADN formalmente incriminados como responsables de esta afección.

Idioma original	Inglés estadounidense
Páginas (desde-hasta)	3161–3166
Número de páginas	5
Publicación	Human Molecular Genetics
Volumen	26
N.º	16
DOI	https://doi.org/10.1093/hmg/ddx199
Estado	Publicada - ago. 15 2017

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@article{666766172ca34c2c89620c42162fbe52,

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

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.",

author = "Carolina Carlosama and {El Zaiat}, Ma{\"e}va and Pati{\~n}o, {Liliana C} and Mateus, {Heidi E} and Veitia, {Reiner A} and Paul Laissue",

year = "2017",

month = aug,

day = "15",

doi = "10.1093/hmg/ddx199",

language = "English (US)",

volume = "26",

pages = "3161–3166",

journal = "Human Molecular Genetics",

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TY - JOUR

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

PY - 2017/8/15

Y1 - 2017/8/15

N2 - 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.

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.

U2 - 10.1093/hmg/ddx199

DO - 10.1093/hmg/ddx199

M3 - Article

C2 - 28541421

SN - 0964-6906

VL - 26

SP - 3161

EP - 3166

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 16

ER -

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

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