<i>DMC1</i> mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing

He, Wen‐Bin; Tu, Chaofeng; Liu, Qiang; Meng, Lanlan; Yuan, Shi‐Min; Luo, Aixiang; He, Fu‐Sheng; Shen, Juan; Li, Wen; Du, Juan; Zhong, Chang-gao; Lu, Guangxiu; Lin, Ge; Fan, Lu; Tan, Yue‐Qiu

doi:10.1136/jmedgenet-2017-104992

Cited by 100 publications

(64 citation statements)

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“…This is in agreement with the secondary POI observed in the patients, and the residual (medically-assisted) fertility in one of the affected sisters. Our identification of HSF2BP as a gene implicated in POI is in line with recent reports of POI-causing variants in genes that are required for DNA repair and recombination, such as MCM8, MCM9, SYCE1, MSH4, PSMC3IP, FANCM or NBN (AlAsiri et al, 2015;Carlosama et al, 2017;de Vries et al, 2014;Fouquet et al, 2017;He et al, 2018;Tenenbaum-Rakover et al, 2015;Tucker et al, 2018;Wood-Trageser et al, 2014;Zangen et al, 2011).…”

Section: Discussionsupporting

confidence: 90%

“…This supramolecular complex participates in the orderly recruitment of essential players to the DSBs such as the initial binding of RPA to the resected DNA, exchange of RPA by RAD51 in a DSS1-dependent manner, and loading of the complex MEIOB-SPATA22 to the RPA complexes (Martinez et al, 2016;Zhao et al, 2015). Interestingly, genes with recently-identified variants in POI patients are implicated in the repair of induced DSBs at the early stages of meiosis and encode BRCA2-interacting factors, such as MEIOB, DMC1 and HSF2BP, or BRCA2 itself (Caburet et al, 2019a;He et al, 2018). This highlights the crucial importance and the high sensitivity of this particular meiotic step, and the hub role of BRCA2 as a tightly-regulated platform for correct meiotic recombination.…”

Section: Discussionmentioning

confidence: 99%

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A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP

Felipe‐Medina¹,

Caburet

Sánchez-Sáez³

et al. 2020

Preprint

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Felipe-Medina et al. describe a missense variant in the meiotic gene HSF2BP in a consanguineous family with Premature Ovarian Insufficiency, and characterize it as an hypormorphic allele, that in vivo impairs its dimerization with a novel meiotic actor, MIDAP/ C19ORF57, and affect recombination at double-strand DNA breaks. AbstractPrimary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with 3 cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene.Functional analysis of the HSF2BP-S167L variant in mouse, compared to a new HSF2BP knock-out mouse showed that it behaves as a hypomorphic allele. HSF2BP-S167L females show reduced fertility with small litter sizes. To obtain mechanistic insights, we identified C19ORF57/MIDAP as a strong interactor and stabilizer of HSF2BP by forming a higherorder macromolecular structure involving BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L mutation showed a strongly decreased expression of both MIDAP and HSF2BP at the recombination nodules. Although HSF2BP-S167L does not affect heterodimerization between HSF2BP and MIDAP, it promotes a lower expression of both proteins and a less proficient activity in replacing RPA by the recombinases RAD51/DMC1, thus leading to a lower frequency of cross-overs. Our results provide insights into the molecular mechanism of two novel actors of meiosis underlying non-syndromic ovarian insufficiency.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP

Felipe‐Medina¹,

Caburet

Sánchez-Sáez³

et al. 2020

Preprint

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“…Azoospermia is the main cause of male infertility. To date, mutations on several genes, including SYCP3 ,5 NR5A1 ,6 TDRD9 ,7 TAF4B and ZMYND15 ,8 TEX11 ,9 10 DMC1 ,11 TDRD7 ,12 MAGEB4 ,13 SYCE1 ,14 SOHLH1 15 and MCM8 ,16 have been identified as the causes of azoospermia. However, the genetic basis of this defect in most infertility cases remains unknown 2–4 12…”

Section: Introductionmentioning

confidence: 99%

XRCC2 mutation causes meiotic arrest, azoospermia and infertility

et al. 2018

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BackgroundMeiotic homologous recombination (HR) plays an essential role in gametogenesis. In most eukaryotes, meiotic HR is mediated by two recombinase systems: ubiquitous RAD51 and meiosis-specific DMC1. In the RAD51-mediated HR system, RAD51 and five RAD51 paralogues are essential for normal RAD51 function, but the role of RAD51 in human meiosis is unclear. The knockout of Rad51 or any Rad51 paralogue in mice exhibits embryonic lethality. We investigated a family with meiotic arrest, azoospermia and infertility but without other abnormalities.MethodsHomozygosity mapping and whole-exome sequencing were performed in a consanguineous family. An animal model carrying a related mutation was created by using a CRISPR/Cas9 system.ResultsWe identified a 1 bp homozygous substitution (c.41T>C/p.Leu14Pro) on a RAD51 paralogue, namely, XRCC2, in the consanguineous family. We did not detect any XRCC2 recessive mutation in a cohort of 127 males with non-obstructive-azoospermia. Knockin mice with Xrcc2-c.T41C/p.Leu14Pro mutation were generated successfully by the CRISPR/Cas9 method. The homozygotes survived and exhibited meiotic arrest, azoospermia, premature ovarian failure and infertility.ConclusionA XRCC2 recessive mutation causing meiotic arrest and infertility in humans was duplicated with knockin mice. Our results revealed a new Mendelian hereditary entity and provided an experimental model of RAD51-HR gene defect in mammalian meiosis.

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“…Another indicator of whether an allele might cause infertility is allele frequency. As noted by He et al (He et al 2018), the Dmc1 M200V has a high allelic frequency in African populations (12% according to the gnomAD database), which seems incompatible with it being an infertility allele.…”

Section: Discussionmentioning

confidence: 89%

A putative human infertility allele of the meiotic recombinase DMC1 does not affect fertility in mice

Tran

Schimenti

2018

Preprint

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Whole exome or genome sequencing is becoming routine in clinical situations for identifying mutations underlying presumed genetic causes of disease, including infertility. While this is a powerful approach for implicating polymorphisms or de novo mutations in genes plausibly related to the phenotype, a greater challenge is to definitively prove causality. This is a crucial requisite for treatment, especially for infertility, in which validation options are limited. In this study, we created a mouse model of a putative infertility allele, DMC1 M200V

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DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing

Abstract: To the best of our knowledge, this is the first report identifying as the causative gene for human NOA and POI. Furthermore, our pedigree analysis shows an autosomal recessive mode of inheritance for NOA and POI caused by in this family.

Cited by 100 publications

References 50 publications

A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP

A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP

XRCC2 mutation causes meiotic arrest, azoospermia and infertility

A putative human infertility allele of the meiotic recombinase DMC1 does not affect fertility in mice

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