Non-syndromic monogenic male infertility.

Acta Biomed 2019; Vol. 90, Supplement 10: 62-67 DOI: 10.23750/abm.v90i10-S.8762 © Mattioli 1885 Review Non-syndromic monogenic male infertility Giulia Guerri1, Tiziana Maniscalchi2, Shila Barati2, Gian Maria Busetto3, Francesco Del Giudice3, Ettore De Berardinis3, Rossella Cannarella4, Aldo Eugenio Calogero4, Matteo Bertelli2 MAGI’s Lab, Rovereto (TN), Italy; 2 MAGI Euregio, Bolzano, Italy; 3 Department of Urology, University of Rome La Sapienza, Policlinico Umberto I, Rome, Italy; 4 Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy 1 Summary. Infertility is a widespread clinical problem affecting 8-12% of couples worldwide. Of these, about 30% are diagnosed with idiopathic infertility since no causative factor is found. Overall 40-50% of cases are due to male reproductive defects. Numerical or structural chromosome abnormalities have long been associated with male infertility. Monogenic mutations have only recently been addressed in the pathogenesis of this condition. Mutations of specific genes involved in meiosis, mitosis or spermiohistogenesis result in spermatogenic failure, leading to the following anomalies: insufficient (oligozoospermia) or no (azoospermia) sperm production, limited progressive and/or total sperm motility (asthenozoospermia), altered sperm morphology (teratozoospermia), or combinations thereof. Androgen insensitivity, causing hormonal and sexual impairment in males with normal karyotype, also affects male fertility. The genetic causes of non-syndromic monogenic of male infertility are summarized in this article and a gene panel is proposed. (www.actabiomedica.it) Key words: male infertility, oligozoospermia, azoospermia, asthenozoospermia, teratozoospermia, spermatogenic failure, androgen insensitivity syndrome Introduction Infertility is defined as failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse (1). Its prevalence is not negligible, since about 48.5 million couples worldwide do not reach pregnancy after 5 years (2). Overall, about 50% of cases are due to a male factor infertility (3). Genetic causes have been estimated to exist in about 15% of infertile patients, especially in those with azoospermia or severe oligozoospermia (3). Genetic causes of male infertility can be classified as pre-testicular (affecting hypothalamic-pituitary function), testicular (causing dysfunction at testicular level) and post-testicular (leading to obstruction or interfering with ejaculation of sperm). Other causes include androgen resistance and disorders of sexual development. Genetic causes of male infertility are outlined in Table 1. Despite a proper diagnostic work-up, the etiology of male infertility remains elusive in up to 75% of cases (4). In recent years, much effort has been made to investigate new candidate genes responsible for male infertility caused by single-gene mutations (5,6). Several genes involved in meiotic and mitotic divisions and in spermiohistogenesis have been examined as potential targets. They may play a role in the pathogenesis of defects of sperm number (oligozoospermia or azoospermia), motility (asthenozoospermia) or morphology (teratozoospermia) (7). In this review we describe genes belonging to the panels developed by us for the diagnosis of monogenic spermatogenic failure and androgen insensitivity syndrome. 63 Non-syndromic monogenic male infertility Table 1. Main causes of genetic forms of male infertility. • Normosmic hypogonadotropic hypogonadism • Anosmic hypogonadotropic hypogonadism (Kallmann syndrome) Pre-testicular causes • Prader-Willy syndrome • Laurence-Moon-Biedl syndrome • Others Testicular forms • • • • • • Post-testicular causes • Kartagener syndrome • Congenital bilateral deferent duct agenesis • Young syndrome Others • Androgen resistance • Disorders of sexual development Klinefelter syndrome Numerical chromosomal abnormalities Y chromosome microdeletions Chromosomal translocations Down syndrome Myotonic dystrophy (Steinert syndrome) Genes involved in sperm number defects Sperm number defects include azoospermia and oligozoospermia. Azoospermia is the absence of spermatozoa in semen. It affects 1% of the male population and accounts for 20% of all cases of male infertility (8). In about the 40% of patients, spermatogenesis occurs in a regular way but sperm emission is impaired by seminal duct obstruction (obstructive azoospermia) (9); in the other cases, azoospermia is due to spermatogenic failure (non-obstructive azoospermia) (10). Genetic causes of azoospermia include chromosome anomalies (numerical or structural aberrations of autosomal or sexual chromosomes) that affect 5% of all infertile males and 16% of males with azoospermia or oligozoospermia (11). In 5-15% of cases, azoospermia or oligozoospermia is associated with Y chromosome microdeletions; 6-8% of cases with obstructive azoospermia are associated with mutations in the cystic fibrosis transmembrane receptor gene (CFTR) that causes congenital bilateral absence of the vas deferens (11). Point mutations that cause azoospermia were recently found in the following genes: NR5A1, SYCP3, ZMYND15, TAF4B, TEX11 NANOS1, PLK4, MEIOB, SYCE1, USP9Y, SOHLH1, TEX15, HSF2 and KLHL10 (12-19) (Table 2). Frameshift mutations in ZMYND15 cause the SPGF14 phenotype. The protein encoded by this gene is involved in temporally normal haploid gene expression during spermatogenesis (13). A homozygous mutation in SYCE1 is associated with the SPGF15 phenotype. This gene encodes a member of the synaptonemal complex, a structure that physically links homologous chromosomes during meiosis I (14). Mutations in TEX11 have been associated with meiotic arrest and azoospermia with a frequency of 1-15% in the azoospermic males. TEX11-encoded protein regulates the coupling of homologous chromosomes in double-strand DNA repair through formation of the synaptonemal complex and the chiasma during the crossover process (20). A similar role is performed by SYCP3 that has also been found mutated in sterile men (16). SOHLH1 is mutated in some cases of azoospermia and encodes a testicular transcription factor essential for spermatogenesis (21). A mutation in NR5A1, encoding steroidogenic factor 1, has been reported in a Pakistani patient with meiotic arrest and normal levels of follicle-stimulating and luteinizing hormones, and testosterone (22). Finally, a patient with spermatogenesis blocked at the spermatocyte stage had a dominant negative mutation in HSF2, encoding heat shock transcription factor 2 (23). 64 G. Guerri, T. Maniscalchi, S. Barati, et al. Table 2. Genes associated with spermatogenic failure Gene Inheritance OMIM gene OMIM phenotype OMIM or HGMD phenotype ID Spermatogenic defect NR5A1 AR 184757 SPGF8 613957 AZS/OZS SYCP3 AD 604759 SPGF4 270960 AZS/OZS ZMYND15 AR 614312 SPGF14 615842 AZS/OZS TAF4B AR 601689 SPGF13 615841 AZS/OZS TEX11 X (...truncated)