
DOI . ORG {
}
Title[redir]:
Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia | Human Genetics
Description:
Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing in three affected brothers with NOA, their two unaffected brothers and their father, and identified compound heterozygous frameshift variants (one novel and one extremely rare) in Telomere Repeat Binding Bouquet Formation Protein 2 (TERB2) that segregated perfectly with NOA. TERB2 interacts with TERB1 and Membrane Anchored Junction Protein (MAJIN) to form the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for the completion of meiosis and both male and female fertility. Given our novel findings of TERB2 variants in NOA men, along with the integral role of the three MTC proteins in spermatogenesis, we subsequently explored exome sequence data from 1495 NOA men to investigate the role of MTC gene variants in spermatogenic impairment. Remarkably, we identified two NOA patients with likely damaging rare homozygous stop and missense variants in TERB1 and one NOA patient with a rare homozygous missense variant in MAJIN. Available testis histology data from three of the NOA patients indicate germ cell maturation arrest, consistent with mouse phenotypes. These findings suggest that variants in MTC genes may be an important cause of NOA in both consanguineous and outbred populations.
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Keywords {🔍}
article, pubmed, google, scholar, terb, cas, infertility, protein, male, hum, sequencing, variant, genet, central, variants, genetic, human, majin, noa, sequence, exon, httpsdoiorgs, university, data, genes, genome, genetics, telomere, men, nonobstructive, azoospermia, alignment, moesmesmtif, fig, validation, tif, meiotic, tüttelmann, james, conrad, spermatogenesis, family, reprod, nat, krausz, utah, usa, detected, content, research,
Topics {✒️}
month download article/chapter bi-allelic recessive loss ewa rajpert-de meyts genome-wide significance testing article salas-huetos human protein-coding genes haplotype-based variant detection register-based cohort study meiotic telomere movement high-throughput sequencing data related subjects accurate long-read alignment full article pdf inovação em saúde german research foundation meiotic telomere attachment privacy choices/manage cookies male infertility access exome sequencing reveals sabine kliesch exchanging telomere cap salas-huetos andrology-male reproductive health genome analysis toolkit gemini consortium members factors controlling spermatogenesis antibody-based profiling high-resolution phenotyping gov/pubmed/ short-read sequencing disease gene discovery highest-ranked variants impaired spermatogenesis affects majin variants based european economic area multiple sons displayed y-chromosomal microdeletions burrows-wheeler transform nonfluorescent portion oi salt lake city genome aggregation database /cgi-bin/hgpcr ethics declarations conflicts additional information publisher' electronic supplementary material showing strong enrichment define column headers chromosome long arm male factor infertility conditions privacy policy
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headline:Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia
description:Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing in three affected brothers with NOA, their two unaffected brothers and their father, and identified compound heterozygous frameshift variants (one novel and one extremely rare) in Telomere Repeat Binding Bouquet Formation Protein 2 (TERB2) that segregated perfectly with NOA. TERB2 interacts with TERB1 and Membrane Anchored Junction Protein (MAJIN) to form the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for the completion of meiosis and both male and female fertility. Given our novel findings of TERB2 variants in NOA men, along with the integral role of the three MTC proteins in spermatogenesis, we subsequently explored exome sequence data from 1495 NOA men to investigate the role of MTC gene variants in spermatogenic impairment. Remarkably, we identified two NOA patients with likely damaging rare homozygous stop and missense variants in TERB1 and one NOA patient with a rare homozygous missense variant in MAJIN. Available testis histology data from three of the NOA patients indicate germ cell maturation arrest, consistent with mouse phenotypes. These findings suggest that variants in MTC genes may be an important cause of NOA in both consanguineous and outbred populations.
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headline:Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia
description:Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing in three affected brothers with NOA, their two unaffected brothers and their father, and identified compound heterozygous frameshift variants (one novel and one extremely rare) in Telomere Repeat Binding Bouquet Formation Protein 2 (TERB2) that segregated perfectly with NOA. TERB2 interacts with TERB1 and Membrane Anchored Junction Protein (MAJIN) to form the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for the completion of meiosis and both male and female fertility. Given our novel findings of TERB2 variants in NOA men, along with the integral role of the three MTC proteins in spermatogenesis, we subsequently explored exome sequence data from 1495 NOA men to investigate the role of MTC gene variants in spermatogenic impairment. Remarkably, we identified two NOA patients with likely damaging rare homozygous stop and missense variants in TERB1 and one NOA patient with a rare homozygous missense variant in MAJIN. Available testis histology data from three of the NOA patients indicate germ cell maturation arrest, consistent with mouse phenotypes. These findings suggest that variants in MTC genes may be an important cause of NOA in both consanguineous and outbred populations.
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name:University of Utah School of Medicine
address:
name:Andrology and IVF Laboratory, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, USA
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:Andrology and IVF Laboratory, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, USA
name:Institute of Reproductive Genetics, University of Münster, Münster, Germany
name:Institute of Reproductive Genetics, University of Münster, Münster, Germany
name:Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster, Münster, Germany
name:Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster, Münster, Germany
name:i3S-Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
name:IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
name:Departamento de Genética Humana, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisbon, Portugal
name:ToxOmics-Centro de Toxicogenómica e Saúde Humana, Nova Medical School, Lisbon, Portugal
name:Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, USA
name:Utah Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, USA
name:Institute of Medical Informatics, University of Münster, Munster, Germany
name:Andrology and IVF Laboratory, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, USA
name:Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, USA
name:Division of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, USA
name:Division of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, USA
name:Department of Genetics, Washington University School of Medicine, St. Louis, USA
name:Andrology and IVF Laboratory, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, USA
name:Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, USA
name:Andrology and IVF Laboratory, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, USA
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