Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility

Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.

Palavras-chave

Azoospermia Cell Cycle Checkpoints MaleI Infertility Non-obstructive azoospermia (NOA) Phenotype Spermatogenesis Spermatozoa M1AP Doenças Genéticas

URI

http://hdl.handle.net/10400.18/7354

Citação

Am J Hum Genet. 2020 Aug 6;107(2):342-351. doi: 10.1016/j.ajhg.2020.06.010. Epub 2020 Jul 15.

Editora

Cell Press

DOI

10.1016/j.ajhg.2020.06.010

Coleções

DGH - Artigos em revistas internacionais

Licença CC

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