Autosomal Mutations and Spermatogenic Failure


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).

Keywords: male infertility; spermatogenesis; autosomal mutations; rare variants; non‐syndromic infertility

Figure 1.

Overview of human spermatogenesis. In this schematics the process of spermatogenesis is depicted in an overview of a cross‐section of a seminiferous tubule. Male gametes develop within the epithelia (b – Sertoli cells) of the seminiferous tubules in the testis, with differentiation occurring from the wall (a) towards the lumen (c). Diploid GCs undergo several rounds of mitosis giving rise to type A spermatogonia (SPG), to maintain the pool of stem cells and type B SPG that differentiate into primary spermatocytes (SPC I). These cells then go through meiosis I, where recombination of genetic material occurs, and originate haploid secondary spermatocytes (SPCs II). A second round of meiosis originates haploid round spermatids (SPTs) that, through a process called spermiogenesis, acquire sperm cell specialisations and are released (spermiation) into the lumen, becoming testicular SPZ. Testicular sperm cells are immotile and require the unique environment of the epididymis to gain such function. The last step of sperm maturation (capacitation) occurs within the female reproductive tract where SPZ become competent for fertilisation.

Figure 2.

Diagram of longitudinal section of a human spermatozoon. Human male gametes are highly specialized cells with a structure optimised for fertilisation. Sperm cells lack many cytoplasmatic organelles, such as endoplasmic reticulum, Golgi apparatus or ribosomes, but develop a unique secretory vesicle called acrosome which contains many hydrolytic enzymes required for egg penetration. In the nucleus, histones are replaced by protamines to allow DNA compaction into a much reduced volume. The capacity to move in an aqueous medium is provided by a strong flagellum. The mid piece is the region of the cell that powers the flagellum for motility by the presence of a mitochondrial sheath displayed as a spiral structure around the axoneme, resulting from the fusion of individual mitochondria during SPT differentiation. The axoneme is a cytoskeleton structure in the inner core of the flagellum, going from the proximal centriole until the end of the tail. In mammals, it consists of two singlet microtubules surrounded by nine microtubule doublets and due to this distinctive organisation and the presence of axonemal dyneins, is the structure responsible for generating movement of the flagellum. The unique organisation and specialisation of cellular structures in the spermatozoon allows its hypermotility and the proper fertilisation of the female egg.



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Further Reading

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Tuttelmann F, Rajpert‐De Meyts E, Nieschlag E and Simoni M (2007) Gene polymorphisms and male infertility – a meta‐analysis and literature review. Reproductive BioMedicine Online 15(6): 643–658.

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Lima, Ana C, and Lopes, Alexandra M(Jun 2014) Autosomal Mutations and Spermatogenic Failure. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025310]