Autosomal Mutations and Spermatogenic Failure

Abstract

Male infertility is commonly due to an impairment in the production of viable sperm, capable of fertilisation. Spermatogenic failure can manifest in its most severe form by an absence of mature sperm or, more often, by a reduction in sperm counts, as an isolated phenotype or in combination with abnormalities in sperm motility and morphology. In only a fraction of patients with primary spermatogenic failure can an underlying genetic cause be identified, such as karyotype abnormalities and Y chromosome microdeletions. However, a small number of autosomal genes harbour rare variants/mutations with strong evidence of their impact in primary spermatogenic failure in otherwise healthy men ( SYCP3 , NR5A1 , DMRT1 , CATSPER , DNAI1 , DNAH5 , DNAH11 , SLC26A8 , AURKC , SPATA16 , DPY19L2 , KLHL10 and SEPT12 ). Even though the clinical relevance of the majority of these variants is still uncertain, they represent promising markers for spermatogenesis deficits. Key Concepts: Spermatogenesis is an intricate process and a large number of genes on the autosomes are involved. The etiopathogenesis of severe spermatogenic failure in otherwise healthy men is complex and still largely unknown. A highly penetrant genetic variant resulting in male infertility should be rare in a population. Validation of potentially deleterious variants must rely on the analysis of a large number of patients, replication in cohorts of different ethnicity, familial data and functional assays. Spermatogenic failure may result from the disturbance of many different processes (gonadal formation and maintenance, meiosis and morphological differentiation of gametes).

Rare double sex and mab-3-related transcription factor 1 regulatory variants in severe spermatogenic failure

“…It is estimated that NOA accounts for 10-15% of the cases of male infertility, affecting 1% of male individuals worldwide (Practice Committee of American Society for Reproductive Medicine in collaboration with Society for Male Reproduction and Urology 2008). Importantly, over the past years several studies have been showing that a significant portion of the genes involved in severe spermatogenic failure (SSF) are spread throughout the genome rather than restricted to the sex chromosomes [Reviewed in (Lima & Lopes 2014)]. One particular genomic region (9p), harboring the doublesex and mab-3 related transcription factor (DMRT) gene cluster, has been linked with disorders of sex development (Õunap et al 2004, Raymond et al 1999, Tannour-Louet et al 2010, Veitia et al 1997).…”

Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia

“…Despite many decades of research in the field of male infertility genetics, only a few genes have been identified to be causal for male infertility when mutated (Lima & Lopes, 2014), namely CFTR (Chillon et al, 1995), DDX3Y (Foresta, Ferlin, & Moro, 2000), SYCP3 (Miyamoto et al, 2003), TEX11 (Yang et al, 2015;Yatsenko et al, 2015), AURKC (Dieterich et al, 2007;Dieterich et al, 2009), and DPY19L2 (Elinati et al, 2012;Koscinski et al, 2011). These genes play crucial roles in the development of the vas deferentia (CFTR) (Claustres, 2005), the pre-meiotic germ cell formation (DDX3Y) (Ramathal et al, 2015), synaptonemal complex formation during meiosis (SYPC3 and TEX11) (Dobson, Pearlman, Karaiskakis, Spyropoulos, & Moens, 1994;Yang et al, 2008), cytokinesis and chromosomal segregation during meiosis (AURKC) (Yan et al, 2005), and acrosome formation in maturing sperm cells (DPY19L2) (Pierre et al, 2012).…”