TY - JOUR
T1 - A truncating MEIOB mutation responsible for familial primary ovarian insufficiency abolishes its interaction with its partner SPATA22 and their recruitment to DNA double-strand breaks
AU - Caburet, Sandrine
AU - Todeschini, Anne Laure
AU - Petrillo, Cynthia
AU - Martini, Emmanuelle
AU - Farran, Nada D.
AU - Legois, Bérangère
AU - Livera, Gabriel
AU - Younis, Johnny S.
AU - Shalev, Stavit
AU - Veitia, Reiner A.
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/4
Y1 - 2019/4
N2 - Background: Primary Ovarian Insufficiency (POI), a major cause of infertility, affects about 1–3% of women under forty years of age. Although there is a growing list of causal genetic alterations, POI remains mostly idiopathic. Methods: We performed exome sequencing (WES)of two sisters affected with POI, one unaffected sister and their mother from a consanguineous family. We assessed the impact of the identified MEIOB variant with a minigene assay and by sequencing illegitimate transcripts from the proband's leukocytes. We studied its functional impact on the interaction between MEIOB with its partner SPATA22 and their localization to DNA double-strand breaks (DSB). Findings: We identified a homozygous variant in the last base of exon 12 of MEIOB, which encodes a factor essential for meiotic recombination. This variant was predicted to strongly affect MEIOB pre-mRNA splicing. Consistently, a minigene assay showed that the variant induced exon 12 skipping, which was confirmed in vivo in the proband's leukocytes. Aberrant splicing leads to the production of a C-terminally truncated protein that cannot interact with SPATA22, abolishing their recruitment to DSBs. Interpretation: This truncating MEIOB variant is expected to provoke meiotic defects and a depleted follicular stock, as in Meiob −/− mice. This is the first molecular defect reported in a meiosis-specific single-stranded DNA-binding protein (SSB)responsible for POI. We hypothesise that alterations in other SSB proteins could explain cases of syndromic or isolated ovarian insufficiency. Fund: Université Paris Diderot, Fondation pour la Recherche Médicale, Fondation ARC contre le cancer, Commissariat à l'Energie Atomique and Institut Universitaire de France.
AB - Background: Primary Ovarian Insufficiency (POI), a major cause of infertility, affects about 1–3% of women under forty years of age. Although there is a growing list of causal genetic alterations, POI remains mostly idiopathic. Methods: We performed exome sequencing (WES)of two sisters affected with POI, one unaffected sister and their mother from a consanguineous family. We assessed the impact of the identified MEIOB variant with a minigene assay and by sequencing illegitimate transcripts from the proband's leukocytes. We studied its functional impact on the interaction between MEIOB with its partner SPATA22 and their localization to DNA double-strand breaks (DSB). Findings: We identified a homozygous variant in the last base of exon 12 of MEIOB, which encodes a factor essential for meiotic recombination. This variant was predicted to strongly affect MEIOB pre-mRNA splicing. Consistently, a minigene assay showed that the variant induced exon 12 skipping, which was confirmed in vivo in the proband's leukocytes. Aberrant splicing leads to the production of a C-terminally truncated protein that cannot interact with SPATA22, abolishing their recruitment to DSBs. Interpretation: This truncating MEIOB variant is expected to provoke meiotic defects and a depleted follicular stock, as in Meiob −/− mice. This is the first molecular defect reported in a meiosis-specific single-stranded DNA-binding protein (SSB)responsible for POI. We hypothesise that alterations in other SSB proteins could explain cases of syndromic or isolated ovarian insufficiency. Fund: Université Paris Diderot, Fondation pour la Recherche Médicale, Fondation ARC contre le cancer, Commissariat à l'Energie Atomique and Institut Universitaire de France.
KW - Exon skipping
KW - Female infertility
KW - MEIOB
KW - Meiotic recombination
KW - Primary ovarian insufficiency
UR - http://www.scopus.com/inward/record.url?scp=85064224265&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2019.03.075
DO - 10.1016/j.ebiom.2019.03.075
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C2 - 31000419
AN - SCOPUS:85064224265
SN - 2352-3964
VL - 42
SP - 524
EP - 531
JO - EBioMedicine
JF - EBioMedicine
ER -