XRCC2 mutation causes meiotic arrest, azoospermia and infertility

Yang, Yongjia; Guo, Jihong; Dai, Lei; Zhu, Yimin; Hu, Hao; Tan, Lihong; Chen, Weijian; Liang, Desheng; He, Jingliang; Tu, Min; Wang, Kewei; Wu, Lingqian

doi:10.1136/jmedgenet-2017-105145

Cited by 59 publications

(43 citation statements)

References 43 publications

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“…We used functional analysis to explore the effects of this mutation further. Firstly, total RNA was extracted from patients' blood, and reverse transcription PCR (RT‐PCR) showed this variant caused partially aberrant splicing (Figure D), consistent with the earlier report . In addition, immunofluorescence revealed that γH2AX staining appeared prominently in the spermatocytes undergoing preleptotene to zygotene in the seminiferous tubules of the male patient, and no sex body was observed (Figure E).…”

supporting

confidence: 85%

“…These results suggested that spermatogenesis was blocked in the zygotene stage in our male patient. Furthermore, terminal dexynucleotidyl transferase(TdT)‐mediated dUTP nick end labeling (TUNEL) assay showed a significant increase in apoptotic germ cells in his seminiferous tubules, similar to Xrcc2 knock‐in mice (Figure F) …”

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confidence: 80%

“…Meiotic homologous recombination, which is mediated by the ubiquitous RAD51 and meiosis‐specific DMC1 recombinase systems, is a vital process, for both oogenesis and spermatogenesis. A c.41T>C (p.Leu14Pro) substitution in XRCC2 , a paralog of RAD51 , was recently reported to be associated with non‐obstructive azoospermia (NOA) in humans . Here, we found that this gene could also cause premature ovarian insufficiency (POI).…”

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confidence: 84%

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XRCC2 mutation causes premature ovarian insufficiency as well as non‐obstructive azoospermia in humans

Zhang

et al. 2018

Clinical Genetics

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XRCC2 mutation causes premature ovarian insufficiency as well as non‐obstructive azoospermia in humans

Zhang

et al. 2018

Clinical Genetics

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“…These three genes are highly expressed in meiotic tissues in animals [28–30] and plants [31–33]. In humans, mutation in XRCC2 has been linked to meiotic arrest, azoospermia and infertility [34] and absence of RAD51B or RAD51D lead to meiotic defects in the moss Physcomitrella patens and rice, respectively [35–37]. The Arabidopsis xrcc2 mutant and, to a lesser extent rad51b , have been associated with increased meiotic recombination rates, but all three mutants are fully fertile and present no detectable meiotic defects [24, 38–40].…”

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confidence: 99%

RAD54 is essential for RAD51-mediated repair of meiotic DSB in Arabidopsis

Sanchez-Rebato

Bouatta

Gallego

et al. 2020

Preprint

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22An essential component of the homologous recombination machinery in eukaryotes, 23 the RAD54 protein is a member of the SWI2/SNF2 family of helicases with dsDNA-dependent 24 ATPase, DNA translocase, DNA supercoiling and chromatin remodelling activities. It is a motor 25 protein that translocates along dsDNA and performs multiple functions in homologous 26 recombination. In particular, RAD54 is an essential cofactor for regulating RAD51 activity. It 27 stabilizes the RAD51 nucleofilament, remodels nucleosomes, and stimulates homology search 28 and strand invasion activity of RAD51. Accordingly, deletion of RAD54 has dramatic 29 consequences on DNA damage repair in mitotic cells. In contrast, its role in meiotic 30 recombination is less clear. 31RAD54 is essential for meiotic recombination in Drosophila and C. elegans, but plays 32 minor roles in yeast and mammals. We present here characterization of the roles of RAD54 in 33 meiotic recombination in the model plant Arabidopsis thaliana. Absence of RAD54 has no 34 detectable effect on meiotic recombination in otherwise wild-type plants but RAD54 becomes 35 essential for meiotic DSB repair in absence of DMC1. In Arabidopsis, dmc1 mutants have an 36 achiasmate meiosis, in which RAD51 repairs meiotic DSBs. Absence of RAD54 in dmc1 37 mutants leads to meiotic chromosomal fragmentation. The action of RAD54 in meiotic RAD51 38 activity is thus downstream of the role of RAD51 in supporting the activity of DMC1. Equivalent 39 analyses show no effect on meiosis of combining dmc1 with the mutants of the RAD51-40 mediators RAD51B, RAD51D and XRCC2. 41RAD54 is thus required for repair of meiotic DSBs by RAD51 and the absence of 42 meiotic phenotype in rad54 plants is a consequence of RAD51 playing a RAD54-independent 43 supporting role to DMC1 in meiotic recombination. 44 45 46 3 47 Author Summary48 Homologous recombination is a universal pathway which repairs broken DNA molecules 49 through the use of homologous DNA templates. It is both essential for maintenance of genome 50 stability and for the generation of genetic diversity through sexual reproduction. A central step 51 of the homologous recombination process is the search for and invasion of a homologous 52 intact DNA sequence that will be used as template. This key step is catalysed by the RAD51 53 recombinase in somatic cells and RAD51 and DMC1 in meiotic cells, assisted by a number of 54 associated factors. Among these, the chromatin-remodelling protein RAD54 is a required 55 cofactor for RAD51 in mitotic cells. Understanding of its role during meiotic recombination 56 however remains elusive. We show here that RAD54 is required for repair of meiotic double 57 strand breaks by RAD51 in the plant Arabidopsis thaliana, and this function is downstream of 58 the meiotic role of RAD51 in supporting the activity of DMC1. These results provide new 59 insights into the regulation of the central step of homologous recombination in plants and very 60 probably also other multicellular eukaryotes. 61 4 62 Introduction 63 Homolo...

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“…8 The incidence of genetic disorders in patients with MA is as high as 45%, as shown by chromosome analysis and Y chromosome microdeletion detection. 8 Monogenic [9][10][11][12][13][14][15][16] However, the genetic factors associated with the majority of MA cases remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Bi-allelic SHOC1 loss-of-function mutations cause meiotic arrest and non-obstructive azoospermia

et al. 2020

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BackgroundThe genetic causes of human idiopathic non-obstructive azoospermia (NOA) with meiotic arrest remain unclear.MethodsTwo Chinese families with infertility participated in the study. In family 1, two brothers were affected by idiopathic NOA. In family 2, the proband was diagnosed with idiopathic NOA, and his elder sister suffered from infertility. Whole-exome sequencing (WES) was conducted in the two patients in family 1, the proband in family 2 and 362 additional sporadic patients with idiopathic NOA. Sanger sequencing was used to verify the WES results. Periodic acid–Schiff (PAS), immunohistochemistry (IHC) and meiotic chromosomal spread analyses were carried out to evaluate the stage of spermatogenesis arrested in the affected cases.ResultsWe identified compound heterozygous loss of function (LoF) variants of SHOC1 (c.C1582T:p.R528X and c.231_232del:p.L78Sfs*9, respectively) in both affected cases with NOA from family 1. In family 2, homozygous LoF variant in SHOC1 (c.1194delA:p.L400Cfs*7) was identified in the siblings with infertility. PAS, IHC and meiotic chromosomal spread analyses demonstrated that the spermatogenesis was arrested at zygotene stage in the three patients with NOA. Consistent with the autosomal recessive mode of inheritance, all of these SHOC1 variants were inherited from heterozygous parental carriers. Intriguingly, WES of 362 sporadic NOA cases revealed one additional NOA case with a bi-allelic SHOC1 LoF variant (c.1464delT:p.D489Tfs*13).ConclusionTo the best of our knowledge, this is the first report identifying SHOC1 as the causative gene for human NOA. Furthermore, our study showed an autosomal recessive mode of inheritance in the NOA caused by SHOC1 deficiency.

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XRCC2 mutation causes meiotic arrest, azoospermia and infertility

Cited by 59 publications

References 43 publications

XRCC2 mutation causes premature ovarian insufficiency as well as non‐obstructive azoospermia in humans

XRCC2 mutation causes premature ovarian insufficiency as well as non‐obstructive azoospermia in humans

RAD54 is essential for RAD51-mediated repair of meiotic DSB in Arabidopsis

Bi-allelic SHOC1 loss-of-function mutations cause meiotic arrest and non-obstructive azoospermia

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