Genetic pathogenesis of acephalic spermatozoa syndrome: past, present, and future

Abstract

Acephalic spermatozoa syndrome (ASS) is one of the most severe spermatogenic failures of all infertility in men. The cognition of ASS has experienced a tortuous process. Over the past years, with the in-depth understanding of spermatogenesis and the emergence of new genetic research technologies, the unraveling of the genetic causes of spermatogenic failure has become highly active. From these advances, we established a genetic background and made significant progress in the discovery of the genetic causes of ASS. It is important to identify pathogenic genes and mutations in ASS to determine the biological reasons for the occurrence of the disease as well as provide genetic diagnosis and treatment strategies for patients with this syndrome. In this review, we enumerate various technological developments, which have made a positive contribution to the discovery of candidate genes for ASS from the past to the present. Simultaneously, we summarize the known genetic etiology of this phenotype and the clinical outcomes of treatments in the present. Furthermore, we propose perspectives for further study and application of genetic diagnosis and assisted reproductive treatment in the future.

Keywords: acephalic spermatozoa syndrome; genetic pathogenesis; male infertility.

Figure 1

Timeline of the advancement of technologies and the discovery of key genes involved in ASS. Various technological developments were highlighted, which contributed significantly, as well as the discovery of candidate genes of mutations causing ASS according to the timeline. ASS: acephalic spermatozoa syndrome; Hook1: hook microtubule tethering protein 1; Prss21: serine protease 21; Oaz3: ornithine decarboxylase antizyme 3; Cntrob: centrobin, centriole duplication and spindle assembly protein; Ift88: intraflagellar transport 88; CRISPR/Cas9: clustered regularly interspaced short palindromic repeats/CRISPR-associated 9; Odf1: outer dense fiber of sperm tails 1; Spata6: spermatogenesis associated 6; SUN5: Sad1 and UNC84 domain containing 5; PMFBP1: polyamine-modulated factor 1 binding protein 1; TSGA10: testis-specific gene antigen 10; BDRT: bromodomain testis-specific protein; DNAH6: dynein axonemal heavy chain 6; CEP112: centrosomal protein 112.

Figure 2

A schematic diagram of normal human spermatozoa. The black box represents the sperm HTCA, and defects in which may cause ASS. The marked parts are what we known and others need us to explore further. ASS: acephalic spermatozoa syndrome; SUN5: Sad1 and UNC84 domain containing 5; PMFBP1: polyamine-modulated factor 1 binding protein 1; SPATA6: spermatogenesis associated 6; HTCA: head–tail coupling apparatus.