Analysis of the Meiotic Recombination Gene<i>REC8</i>for Sequence Variations in a Population with Severe Male Factor Infertility

Griffin, James B.; Emery, Benjamin R.; Christensen, Greg L.; Carrell, Douglas T.

doi:10.1080/19396360802061317

Cited by 13 publications

(13 citation statements)

References 6 publications

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“…3,49 Several other studies have investigated genes including SYCP3, SPO11, FKBP6, BOULE, H2AX and REC8, but have failed to identify any disease-causing mutations. 3,[50][51][52][53][54][55][56][57] The initiation of meiotic recombination is regulated in a large part by the protein SPO11. The SPO11 protein is a type II topoisomerase required for DSB formation in the leptotene stage.…”

Section: Meiotic Recombinationmentioning

confidence: 99%

Meiotic recombination and male infertility: from basic science to clinical reality?

Hann¹,

Lau²,

Tempest³

2011

Asian J Androl

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Infertility is a common problem that affects approximately 15% of the population. Although many advances have been made in the treatment of infertility, the molecular and genetic causes of male infertility remain largely elusive. This review will present a summary of our current knowledge on the genetic origin of male infertility and the key events of male meiosis. It focuses on chromosome synapsis and meiotic recombination and the problems that arise when errors in these processes occur, specifically meiotic arrest and chromosome aneuploidy, the leading cause of pregnancy loss in humans. In addition, meiosis-specific candidate genes will be discussed, including a discussion on why we have been largely unsuccessful at identifying disease-causing mutations in infertile men. Finally clinical applications of sperm aneuploidy screening will be touched upon along with future prospective clinical tests to better characterize male infertility in a move towards personalized medicine.

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Section: Meiotic Recombinationmentioning

confidence: 99%

Meiotic recombination and male infertility: from basic science to clinical reality?

Hann¹,

Lau²,

Tempest³

2011

Asian J Androl

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“…Indeed, although some infertility studies have identified disease-causing mutations, [4][5][6] others have failed to identify any causal mutations, possibly due to the heterogeneous etiology of infertility. [7][8][9][10][11][12][13][14] Even when samples are appropriately collected from patients with a meiotic defect, this complicated biological process in prophase I is mediated by numerous meiotic genes responsible for homologous recombination, synapsis or sister chromatid cohesion. Indeed, even in yeast it is estimated that hundreds of genes may be involved in the meiotic process.…”

Section: Introductionmentioning

confidence: 99%

Screening of genes involved in chromosome segregation during meiosis I: toward the identification of genes responsible for infertility in humans

et al. 2010

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Prophase I of male meiosis during early spermatogenesis involves dynamic chromosome segregation processes, including synapsis, meiotic recombination and cohesion. Genetic defects in the genes that participate in these processes consistently cause reproduction failure in mice. To identify candidate genes responsible for infertility in humans, we performed gene expression profiling of mouse spermatogenic cells undergoing meiotic prophase I. Cell fractions enriched in spermatogonia, leptotene/zygotene spermatocytes or pachytene spermatocytes from developing mouse testis were separately isolated by density gradient sedimentation and subjected to microarray analysis. A total of 726 genes were identified that were upregulated in leptotene/zygotene spermatocytes. To evaluate the screening efficiency for meiosis-specific genes, we randomly selected 12 genes from this gene set and characterized each gene product using reverse transcription (RT)-PCR of RNA from gonadal tissues, in situ hybridization on testicular tissue sections and subcellular localization analysis of the encoded protein. Four of the 12 genes were confirmed as genes expressed in meiotic stage and 2 of these 4 genes were novel, previously uncharacterized genes. Among the three confirmation methods that were used, RT-PCR appeared to be the most efficient method for further screening. These 726 candidates for human infertility genes might serve as a useful resource for next-generation sequencing combined with exon capture by microarray.

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“…C). Despite the scarcity of studies in humans (Oud et al ., ), the same variant was previously described in a patient with NOA, although then it was not considered relevant for male infertility (Griffin et al ., ; Hann et al ., ). In the same patient, we identified a potentially pathogenic homozygous variant (c.22C>G, ClinVar SCV000987206.1) in the gene SYCE1L (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…While functional studies have reported REC8's important role during meiosis, they have failed to identify causal mutations (Hann et al ., ). Coincidentally, the same variant we found in patient M1809, c.91C>T, has already been reported in a single patient with NOA (Griffin et al ., ). When this variant was described, it was considered as polymorphism due to its high frequency of 0.5 in the European population (Griffin et al ., ) but, according to ESP, 1000 genomes, and gnomAD, its maximum population frequency is 0.005.…”

Section: Discussionmentioning

confidence: 97%

“…Coincidentally, the same variant we found in patient M1809, c.91C>T, has already been reported in a single patient with NOA (Griffin et al ., ). When this variant was described, it was considered as polymorphism due to its high frequency of 0.5 in the European population (Griffin et al ., ) but, according to ESP, 1000 genomes, and gnomAD, its maximum population frequency is 0.005. As it is indeed a rare variant, described for the second time in a patient with NOA, we propose this is a causal variant of male infertility.…”

Section: Discussionmentioning

confidence: 99%

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Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes

et al. 2019

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Background The routine genetic analysis for diagnosing male infertility has not changed over the last twenty years, and currently available tests can only determine the etiology of 4% of unselected infertile patients. Thus, to create new diagnostic assays, we must better understand the molecular and genetic mechanisms of male infertility. Although next‐generation sequencing allows for simultaneous analysis of hundreds of genes and the discovery of novel candidates related to male infertility, so far only a few gene candidates have enough sound evidence to support the gene–disease relationship. Objective Since complementary studies are required to validate genes, we aimed to analyze the presence of potentially pathogenic rare variants in a set of candidate genes related to azoospermia in a hitherto understudied South American population. Subjects and Methods We performed whole exome sequencing in a group of 16 patients with non‐obstructive azoospermia from Ribeirão Preto, Brazil. Based on a recent systematic review of monogenic causes of male infertility, we selected a set of 37 genes related to azoospermia, Sertoli‐Cell‐Only histology, and spermatogenic arrest to analyze. The identified variants were confirmed by Sanger sequencing, and their functional consequence was predicted by in silico programs. Results We identified potential pathogenic variants in seven genes in six patients. Two variants, c.671A>G (p.(Asn224Ser)) in DMRT1 and c.91C>T (p.(Arg31Cys)) in REC8, have already been described in association with azoospermia. We also found new variants in genes that already have moderate evidence of being linked to spermatogenic failure (TEX15, KLHL10), in genes with limited evidence (DNMT3B, TEX14) and in one novel promising candidate gene that has no evidence so far (SYCE1L). Discussion Although this study included a small number of patients, the process of rationally selecting genes allowed us to detect rare potentially pathogenic variants, providing supporting evidence for validating candidate genes associated with azoospermia.

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Analysis of the Meiotic Recombination GeneREC8for Sequence Variations in a Population with Severe Male Factor Infertility

Cited by 13 publications

References 6 publications

Meiotic recombination and male infertility: from basic science to clinical reality?

Meiotic recombination and male infertility: from basic science to clinical reality?

Screening of genes involved in chromosome segregation during meiosis I: toward the identification of genes responsible for infertility in humans

Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes

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