Genetic causes of male infertility: snapshot on morphological abnormalities of the sperm flagellum

Abstract

Male infertility due to Multiple Morphological Abnormalities of the sperm Flagella (MMAF), is characterized by nearly total asthenozoospermia due to the presence of a mosaic of sperm flagellar anomalies, which corresponds to short, angulated, absent flagella and flagella of irregular calibre. In the last four years, 7 novel genes whose mutations account for 45% of a cohort of 78 MMAF individuals were identified: DNAH1, CFAP43, CFAP44, CFAP69, FSIP2, WDR66 (CFAP251), AK7. This successful outcome results from the efficient combination of high-throughput sequencing technologies together with robust and complementary approaches for functional validation, in vitro, and in vivo using the mouse and unicellular model organisms such as the flagellated parasite T. brucei. Importantly, these genes are distinct from genes responsible for Primary Ciliary Dyskinesia (PCD), an autosomal recessive disease associated with both respiratory cilia and sperm flagellum defects, and their mutations therefore exclusively lead to male infertility. In the future, these genetic findings will definitely improve the diagnosis efficiency of male infertility and might provide genotype-phenotype correlations, which could be helpful for the prognosis of intracytoplasmic sperm injection (ICSI) performed with sperm from MMAF patients. In addition, functional study of these novel genes should improve our knowledge about the protein networks and molecular mechanisms involved in mammalian sperm flagellum structure and beating.

Keywords: AK; CFAP; DNAH; Genetic; MMAF; Male infertility; Sperm; WDR.

Fig. 1

Morphological defects of the MMAF phenotype. (a) control individual; (b) MMAF individual. Picture from Aminata Touré. Analysis by photon microscopy shows the presence of a mosaic of morphological defects in semen from MMAF patients; in particular, sperm cells with absent (#) and short flagella (*)

Fig. 2

Ultrastructural defects of the MMAF phenotype. a, d control individual; (b, c, e, f) MMAF individual. Pictures from Aminata Touré. a Human spermatozoa with the head on the left, and the flagellum on the right side. The flagellum is divided into two main compartments: the midpiece, which comprises the mitochondrial sheath, and the principal piece, characterized by the presence of a fibrous sheath surrounding the axoneme. b, c Sperm from MMAF individual display incomplete flagellum with short midpiece and abnormal fibrous sheath disposition (b); some sperm lack flagellum and display a large cytoplasmic bag with unassembled axonemal and peri-axonemal components (c). d Transversal section of the axoneme showing the regular microtubule organization with 9 microtubule doublets surrounding the central pair (9 + 2), in normal sperm. e, f In MMAF individual, the axoneme often display a lack of the central pair or total disorganization. Ac: acrosome; Ax: axoneme; CP: central pair, ODF: outer dense fibers; FS: fibrous sheath; LC: longitudinal column, MTD: microtubule doublets, M: mitochondria; N: nucleus