Genetic pathogenesis of acephalic spermatozoa syndrome: past, present, and future / 亚洲男科学杂志(英文版)

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.

Biallelic mutations in spermatogenesis and centriole-associated 1 like (SPATC1L) cause acephalic spermatozoa syndrome and male infertility / 亚洲男科学杂志(英文版)

Acephalic spermatozoa syndrome is a rare type of teratozoospermia that severely impairs the reproductive ability of male patients, and genetic defects have been recognized as the main cause of acephalic spermatozoa syndrome. Spermatogenesis and centriole-associated 1 like (SPATC1L) is indispensable for maintaining the integrity of sperm head-to-tail connections in mice, but its roles in human sperm and early embryonic development remain largely unknown. Herein, we conducted whole-exome sequencing (WES) of 22 infertile men with acephalic spermatozoa syndrome. An in silico analysis of the candidate variants was conducted, and WES data analysis was performed using another cohort consisting of 34 patients with acephalic spermatozoa syndrome and 25 control subjects with proven fertility. We identified biallelic mutations in SPATC1L (c.910C>T:p.Arg304Cys and c.994G>T:p.Glu332X) from a patient whose sperm displayed complete acephalia. Both SPATC1L variants are rare and deleterious. SPATC1L is mainly expressed at the head-tail junction of elongating spermatids. Plasmids containing pathogenic variants decreased the level of SPATC1L in vitro. Moreover, none of the patient's four attempts at intracytoplasmic sperm injection (ICSI) resulted in a transplantable embryo, which suggests that SPATC1L defects might affect early embryonic development. In conclusion, this study provides the first identification of SPATC1L as a novel gene for human acephalic spermatozoa syndrome. Furthermore, WES might be applied for patients with acephalic spermatozoa syndrome who exhibit reiterative ICSI failures.

Genetic analysis of three cases of acephalic spermatozoa syndrome caused by SUN5 mutation and the outcome of assisted reproductive technology / 北京大学学报(医学版)

To explore the genetic causes of 3 male infertility patients with acephalospermia and the outcome of assisted reproductive technology. Clinical diagnosis, sperm morphology examination, sperm transmission electron microscopy examination were performed on 3 patients, and the whole exome sequencing technology was used for screening, Sanger sequencing verification, mutation pathogenicity analysis, and protein sequence homology comparison. Assisted reproductive technology was implemented to assist pregnancy treatment. The 3 patients were all sporadic infertile men, aged 25, 42 and 26 years, and there was no obvious abnormality in the general physical examination. Male external genitalia developed normally, bilateral testicles were normal in volume, and bilateral epididymis and spermatic vein were palpated without nodules, cysts, and tenderness. Repeated semen analysis showed that a large number of immature sperm could be seen, and they had the ability to move. The SUN5 gene of the 3 male infertile patients was a case of homozygous missense mutation c.7C>T (p.Arg3Trp), a case of compound heterozygous missense mutation c.1067G>A (p.Arg356His) and nonsense mutation c.216G>A (p.Trp72*) and a case of homozygous missense mutation c.1043A>T (p.Asn348Ile), of which c.7C>T (p.Arg3Trp) and c.1067G>A (p.Arg356His) were new variants that had not been reported. SIFT, Mutation Taster and PolyPhen-2 software function prediction results were all harmful, the nonsense mutation c.216G>A (p.Trp72*) led to the premature termination of peptide chain synthesis which might have a greater impact on protein function. The homology regions in the protein sequence homology alignment were all highly conserved.The 3 male patients and their spouses obtained 4 biological offspring through intracytoplasmic sperm injection, all of which were boys, and one of them was a twin.Three male infertile patients might be caused by SUN5 gene mutations. Such patients could obtain their biological offspring through assisted reproductive technology. It was still necessary to pay attention to the genetic risk of ASS, it was recommended that both men and women conduct genetic counseling and screening at the same time. In clinical diagnosis, whole exome sequencing technology could be used to perform auxiliary examinations to determine the treatment plan and assisted reproductive methods as soon as possible to reduce the burden on the family and society. The newly discovered mutation sites of SUN5 gene provided clues and directions for elucidating the pathogenic mechanism, and at the same time expanded the pathogenic mutation spectrum of ASS.