Acephalic Spermatozoa Syndrome
Written by Ben Bunting: BA(Hons), PGCert.
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Among the many types of spermatozoa syndromes, the acephalic spermatozoa syndrome is one that is especially debilitating. It causes severe and prolonged symptoms, and can affect the way in which the semen is formed. Some of the most serious symptoms include a lack of libido, sexual dysfunction, irregular sperm production, and difficulty in conception. If left untreated, it can lead to a variety of medical problems, including miscarriage and premature birth. The good news is that there are treatment options for this condition.
What is ACEphalic spermatozoa syndrome?
ACEphalic spermatozoa syndrome (ASS) is one of the most severe forms of teratozoospermia. It results in male infertility and is defined as spermatozoa with decapitated flagella. Although this condition has a genetic cause, its genetic mechanism is still unclear. However, the identification of two genes involved in acephalic spermatozoa syndrome has become possible thanks to new biological techniques.
In human spermatozoa, dyneins are microtubule-associated motor protein complexes that convert chemical energy into mechanical energy and generate force on microtubules. These microtubule-associated motor proteins are associated with sperm head-tail attachment. These microtubule-associated motor protein complexes also contribute to the movement of cilia and ciliary membranes.
DNAJB13 is a gene that plays a critical role in spermiogenesis. It is mainly expressed in adult testes. It is localized at the tip of acephalic flagella in mature spermatozoa. During spermiogenesis, DNAJB13 migrated to the flagella and participated in the process of sperm head-tail integration. The expression of DNAJB13 in mature spermatozoa is higher than that in the acrosomes.
PMFBP1 is a polyamine modulating factor 1 binding protein that is present at the head-tail coupling apparatus (HTCA). It is involved in sperm head-tail attachment and implantation of the fossa. In PMFBP1-deficient mice, there was a cytoplasm droplet in the top of the flagellum in acephalic spermatozoa.
These findings are important because they suggest that SUN5 and PMFBP1 mutations might be involved in acephalic spermatozoa. However, there are still no details regarding the molecular mechanism of human SUN5 and PMFBP1 mutations.
Symptoms
Symptoms of acephalic spermatozoa syndrome are extremely severe. In this disorder, the heads of the spermatozoa have a nucleus. In some cases, the tails are decapitated. The acrosomes are intact in these spermatozoa. These spermatozoa can be classified into three sub-types based on the degree of acephalicness: type I, which is defined by a lack of centrioles; type II, which is marked by a disruption of the junction between the nuclear envelope and the proximal centriole; and type III, which is characterised by a loose or incomplete head-tail junction.
Next-generation sequencing has made it possible to identify causative gene mutations in a variety of morphological anomalies. Some of these mutations are associated with motility anomalies. One of these mutations has been found to be associated with azoospermia, but it is unclear whether it is involved in the formation of acephalic spermatozoa. In addition, mutations in DNAJB13, which is important for spermiogenesis, have been shown to be associated with acephalic spermatozoa.
These studies have provided evidence that the sperm quality of spermatozoides with acephalic phenotype is poor. In these patients, semen parameters such as number and quality of sperm cells, acrosomal area, and spermatozoon vitality were decreased in comparison to the control group. In particular, the number of spermatozoa in the acrosomal area was more than 20% of the sperm head occupied by acrosome.
In addition, the tails of the spermatozoa had a normal structure of the axoneme and a normal mitochondrial ridge. The basal plate was abnormally disorganized in the heads of these spermatozoa. The lack of a basal plate may interfere with the formation of the implantation fossa. In addition, defects in tail migration and attachment to the head might affect the quality of the spermatozoa.
Two of the affected individuals have compound heterozygous mutations in the SUN5 gene. This gene encodes testis-specific nuclear envelope protein. In acephalic spermatozoa, the mRNA for SUN5 was prematurely terminated. In these spermatozoa, the axonemal dynein heavy chain (TSGA10) was not present. In these spermatozoa, SUN5 may be involved in sperm head-tail attachment. In this study, SUN5 was sequenced in three unrelated acephalic spermatozoa patients. These mutations were identified as c.475C-T (p.Arg159*) and c.475T (p.Val165). These mutations resulted in a premature stop codon in the SUN5 mRNA. This might lead to a truncated protein. In addition, the C-terminus of the TSGA10 was also lost, which might impair its function.
The researchers concluded that the phenotype of acephalic spermatozoa is genetically inherited and has monogenic inheritance. However, a more functional study is necessary to determine the cellular mechanisms that contribute to sperm head-tail attachment. A better understanding of the underlying mechanisms that contribute to sperm morphology will help improve treatments for this disease.
Causes
Various mechanisms have been suggested to explain the formation of acephalic spermatozoa. A study of ultrastructural findings suggests that defects in tail migration may affect the head-tail attachment. In addition, overproduction of membranous vesicles may also contribute to the detachment of the tail from the sperm head. However, more functional studies are necessary to clarify pathogenicity.
SUN5 is one of the genes associated with acephalic spermatozoa syndrome (ASS). SUN5 is encoded by a testis-specific nuclear envelope protein, and is essential for anchoring sperm head to tail. Deficiency in SUN5 leads to sub-type II, which is characterized by a complete detachment of sperm tail.
PMFBP1 is another gene involved in ASS. This protein binds to SUN5 to help connect the coupling apparatus to the sperm head. In the present study, we used direct Sanger sequencing to screen for mutations in the PMFBP1 gene in nine unrelated infertile men. A compound heterozygous mutation in PMFBP1 was identified in two affected individuals. This mutation resulted in premature termination codons at the end of SUN5 mRNA. This could impair the function of TSGA10, a protein involved in sperm axoneme integrity.
In addition, a novel SUN5 mutation, c.475C-T (p.Arg159*), was found in a male patient. This mutation results in a premature stop codon in SUN5 mRNA, resulting in the loss of the c-terminus. It also localizes to exon 8 of the SUN5 gene.
Next-generation sequencing is an effective tool to detect causative gene mutations in morphological or motility abnormalities. In our study, we used this method to identify the genetic variants involved in acephalic spermatozoa phenotype in nine unrelated infertile men. In addition, we conducted a systematic review to identify the clinical outcomes of ICSI in these patients. This study revealed that ICSI is a safe and effective therapeutic strategy for acephalic spermatozoa, but caution should be exercised due to the increased risk of congenital malformations. In addition, couples who decide to undergo ICSI should take into account the possibility of imprinting disorders.
These findings suggest that mutations in the SUN5 and PMFBP1 genes may be responsible for ASS. Therefore, screening for SUN5 mutations in a partner is necessary. In addition, ICSI is a suitable therapeutic approach for patients with SUN5 mutations. ICSI can also be an effective strategy for patients with a compound heterozygous SUN5 mutation. Moreover, ICSI can produce healthy offspring for affected individuals.
Although a number of gene variants have been implicated in acephalic spermatozoa, it is unclear which variants contribute to the phenotype. A systematic review of articles that describe gene variants associated with ASS was performed. These articles were then reviewed by two researchers. All final papers were summarized and the title, abstract, and full texts were reviewed.
Treatments
Several types of teratozoospermia have been identified, including acephalic spermatozoa syndrome, which is characterized by a lack of head and tail attachment. In the human, the disorder is also known as a decapitated sperm defect. The phenotype is caused by genetic defects. It is one of the most severe types of teratozoospermia.
Among the genes involved in the formation of acephalic spermatozoa, DNAJB13 plays an important role. The gene is located on HTCA, and is responsible for the interaction of SUN5. Moreover, mutations of this gene are associated with multiple morphological abnormalities of the sperm flagellum. However, the molecular basis of these mutations has not been clearly understood. A more functional study is necessary to confirm the pathogenicity of these mutations.
Next generation sequencing has made it possible to identify the causative gene mutations for a number of morphological and motility disorders, such as acephalic spermatozoa. The present study aims to review the literature on the genetic alterations associated with acephalic spermatozoa. This research was conducted by two researchers. They reviewed the titles of articles published in the final year of the study and selected eligible articles. They then included the articles in a systematic scoping review. They analyzed the abstracts and the full texts of the final papers.
The results indicated that there was a high frequency of mutations in SUN5, a nuclear envelope protein. The mutated protein was truncated and the mRNA exhibited a premature termination codon. The mutant SUN5 mRNA was found to have an Arg159* sequence, and the mutation was associated with a c.475C-T mutation. The Arg159* mutation shortened the N-terminus of the mRNA and led to a premature stop codon. The mutations were localized to exon 8 of the SUN5 mRNA.
In mice, a mutation in the gene SUN5 causes a decapitated sperm head, but it has not been reported in humans. However, the genetic heterogeneity of this disease may explain the absence of mutations in humans. A sub-type of acephalic spermatozoa, called sub-type II, is characterized by a disruption of the junction between the nuclear envelope and the proximal centriole. This is probably due to strong interactions between the nuclear envelope and the HTCA, which might inhibit the release of DNAJB13 after spermatids. The proximal and distal centrioles are intact in the acephalic sperm, but the tail is disarranged and the implantation fossa is not present.
The TSGA10 gene has also been implicated in acephalic spermatozoa, but the protein was not detected in the sperm. The absence of TSGA10 might affect the function of the axoneme, or impair the midpiece structure.
The sperm from patients with acephalic spermatozoa had a lower vitality compared to the control group. A partial mitochondrial sheath was present in the sperm cells from the detached sperm. It is unclear whether the mitochondrial sheath could be a factor in sperm head-tail attachment, and whether this might be the primary cause of the decapitated spermatozoa.
Conclusion
ACEphalic spermatozoa syndrome (ASS) is a rare teratozoospermia that affects men with primary infertility. It is characterized by the presence of headless spermatozoa in the semen. The disorder is caused by genetic variants in the PMFBP1 and TSGA10 genes. The mutations lead to a loss of function of the protein.
The PMFBP1 gene is located on chromosome 16 and has 27 exons. It is highly expressed in human testes. The variant in this gene has been implicated in the ASS phenotype. The mutation site is at p.C132Afs*3 and is highlighted by the red box.
In the present study, the authors compared the sperm quality of patients with the ASS phenotype with that of individuals without ASS. They found that the ASS patients had a lower fertility rate than those who did not have the defect. A higher proportion of headless spermatozoa was observed in those patients. This finding suggests that there is a genetic basis for the formation of the headless sperm.
Next-generation sequencing has helped to identify the causative gene mutations of morphological defects. The variants in the TSGA10 and PMFBP1 genes have been associated with ASS. However, it is unclear if the variants are responsible for the axoneme impairment. This could be due to nuclear defects that interfere with the formation of the basal plate.
In the present study, seven unrelated subjects with an acephalic spermatozoa phenotype were analyzed. One of them was a man from Tunis who sought a consultation for primary infertility.
