X-Linked <i>TEX11</i> Mutations, Meiotic Arrest, and Azoospermia in Infertile Men

Yatsenko, Alexander N.; Georgiadis, Andrew; Röpke, Albrecht; Berman, Andrea J.; Jaffe, Thomas; Olszewska, Marta; Westernströer, Birgit; Sanfilippo, Joseph S.; Kurpisz, Maciej; Rajkovic, Aleksandar; Yatsenko, Svetlana A.; Kliesch, Sabine; Schlatt, Stefan; Tüttelmann, Frank

doi:10.1056/nejmoa1406192

Cited by 299 publications

(244 citation statements)

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“…Mutations in the X-linked androgen receptor (AR) gene have been shown to be associated with disorders in male sexual differentiation and development (9). More recently, mutations in the X-linked gene, TEX11, have been identified as a cause of meiotic arrest and azoospermia (10,11).…”

Section: Introductionmentioning

confidence: 99%

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

Borgmann

Tüttelmann²,

Dworniczak³

et al. 2016

Hum. Mol. Genet.

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The X-linked reproductive homeobox (RHOX) gene cluster encodes transcription factors preferentially expressed in reproductive tissues. This gene cluster has important roles in male fertility based on phenotypic defects of Rhox-mutant mice and the finding that aberrant RHOX promoter methylation is strongly associated with abnormal human sperm parameters. However, little is known about the molecular mechanism of RHOX function in humans. Using gene expression profiling, we identified genes regulated by members of the human RHOX gene cluster. Some genes were uniquely regulated by RHOXF1 or RHOXF2/2B, while others were regulated by both of these transcription factors. Several of these regulated genes encode we demonstrate how the X-linked RHOX gene cluster may function in normal human spermatogenesis and we provide evidence that it is impaired in human male fertility.

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Section: Introductionmentioning

confidence: 99%

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

Borgmann

Tüttelmann²,

Dworniczak³

et al. 2016

Hum. Mol. Genet.

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“…14) have made a compelling case. Recently, hemizygous deletions of the TEX11 gene, presumably catalyzed by unequal recombination between repetitive elements in the locus, have been linked to maturation arrest and infertility in azoospermic men (15).…”

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confidence: 99%

The genetics of human infertility by functional interrogation of SNPs in mice

Singh

Schimenti

2015

Proc. Natl. Acad. Sci. U.S.A.

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Infertility is a prevalent health issue, affecting ∼15% of couples of childbearing age. Nearly one-half of idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. Traditional methods for studying inheritance, such as genome-wide association studies and linkage analyses, have been confounded by the genetic and phenotypic complexity of reproductive processes. Here we describe an association-and linkagefree approach to identify segregating infertility alleles, in which CRISPR/Cas9 genome editing is used to model putatively deleterious nonsynonymous SNPs (nsSNPs) in the mouse orthologs of fertility genes. Mice bearing "humanized" alleles of four essential meiosis genes, each predicted to be deleterious by most of the commonly used algorithms for analyzing functional SNP consequences, were examined for fertility and reproductive defects. Only a Cdk2 allele mimicking SNP rs3087335, which alters an inhibitory WEE1 protein kinase phosphorylation site, caused infertility and revealed a novel function in regulating spermatogonial stem cell maintenance. Our data indicate that segregating infertility alleles exist in human populations. Furthermore, whereas computational prediction of SNP effects is useful for identifying candidate causal mutations for diverse diseases, this study underscores the need for in vivo functional evaluation of physiological consequences. This approach can revolutionize personalized reproductive genetics by establishing a permanent reference of benign vs. infertile alleles.CRISPR/Cas9 | meiosis | spermatogenesis | cyclin | genome editing

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“…It was reported that male Tex11 ‐knockout mice showed infertility, with azoospermia that was caused by meiotic arrest 107. In 2015, a whole‐genome array comparative genomic hybridization screening study that involved 15 patients with azoospermia was conducted 108. A recurrent 99 kb TEX11 intragenic deletion (Xq13.2) was identified in two unrelated patients.…”

Section: Culprit Genes That Have Been Identified In the X Chromosomementioning

confidence: 99%

“…This loss, which was identical in both the patients with azoospermia, predicts a deletion of 79 amino acids within the SPO22 region. Mutation screening was performed by means of direct Sanger sequencing of the TEX11 open reading frame in the blood and semen samples that had been obtained from 289 patients with azoospermia and from 384 controls 108. This showed five novel TEX11 mutations: three splicing mutations and two missense mutations.…”

Section: Culprit Genes That Have Been Identified In the X Chromosomementioning

confidence: 99%

“…These mutations, which occurred in seven of the men with azoospermia, were absent in the normal controls. Notably, five of those TEX11 mutations were detected in 33 patients with azoospermia that was caused by meiotic arrest 108. An immunohistochemical analysis showed specific cytoplasmic TEX11 protein expression in the late spermatocytes and in the round and elongated spermatids in normal human testes.…”

Section: Culprit Genes That Have Been Identified In the X Chromosomementioning

confidence: 99%

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Human male infertility and its genetic causes

Miyamoto

Minase

Shin

et al. 2017

Reprod Medicine & Biology

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BackgroundInfertility affects about 15% of couples who wish to have children and half of these cases are associated with male factors. Genetic causes of azoospermia include chromosomal abnormalities, Y chromosome microdeletions, and specific mutations/deletions of several Y chromosome genes. Many researchers have analyzed genes in the AZF region on the Y chromosome; however, in 2003 the SYCP3 gene on chromosome 12 (12q23) was identified as causing azoospermia by meiotic arrest through a point mutation.MethodsWe mainly describe the SYCP3 and PLK4 genes that we have studied in our laboratory, and add comments on other genes associated with human male infertility.ResultsUp to now, The 17 genes causing male infertility by their mutation have been reported in human.ConclusionsInfertility caused by nonobstructive azoospermia (NOA) is very important in the field of assisted reproductive technology. Even with the aid of chromosomal analysis, ultrasonography of the testis, and detailed endocrinology, only MD‐TESE can confirm the presence of immature spermatozoa in the testes. We strongly hope that these studies help clinics avoid ineffective MD‐TESE procedures.

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X-Linked TEX11 Mutations, Meiotic Arrest, and Azoospermia in Infertile Men

Cited by 299 publications

References 40 publications

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

The genetics of human infertility by functional interrogation of SNPs in mice

Human male infertility and its genetic causes

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