Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia. Hum Genet 2021 Jan;140(1):217-227
Date
11/20/2020Pubmed ID
33211200Pubmed Central ID
PMC7893731DOI
10.1007/s00439-020-02236-1Scopus ID
2-s2.0-85097044519 (requires institutional sign-in at Scopus site) 29 CitationsAbstract
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.
Author List
Salas-Huetos A, Tüttelmann F, Wyrwoll MJ, Kliesch S, Lopes AM, Goncalves J, Boyden SE, Wöste M, Hotaling JM, GEMINI Consortium, Nagirnaja L, Conrad DF, Carrell DT, Aston KIAuthor
Jay I. Sandlow MD Chair, Professor in the Urologic Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Azoospermia
Cell Cycle Proteins
DNA-Binding Proteins
Exome
Heterozygote
Homozygote
Humans
Male
Meiosis
Membrane Proteins
Mutation, Missense
Phenotype
Spermatogenesis
Telomere
Telomere-Binding Proteins
Testis
