Morphological Abnormalities Of Sperm Flagella Research Articles

The compound heterozygous mutations of CFAP65 cause multiple morphological abnormalities of sperm flagella in infertile men.

The compound heterozygous mutations of CFAP65 cause multiple morphological abnormalities of sperm flagella in infertile men.

P-052 A novel variant in CFAP69 gene causes morphological abnormalities of human sperm flagella with good ART outcomes

Abstract Study question Is there any novel variant in CFAP69 gene related to multiple morphological abnormalities of sperm flagella (MMAF) in humans? Summary answer We identified a loss-of-function variant of CFAP69 in a Chinese man with MMAF and intracytoplasmic sperm injection (ICSI) is favorable for the affected couple. What is known already MMAF is a specific type of asthenoteratozoospermia characterized by immotile and malformed spermatozoa. Genetic defects are the major cause of MMAF, and more than 20 genes have been related to approximately 70% MMAF-affected cases. CFAP69, a cilia- and flagella-associated gene, is abundantly expressed in the testis and associated with infraglabellar transport. To date, four variants in CFAP69 were related to four MMAF patients in the literatures, and the male Cfap69-knockout mice mimicked the infertility and profound flagellum morphology defects phenotype. Study design, size, duration A cohort of 35 infertile Chinese men with MMAF were recruited in the center for reproductive medicine from August 2019 to October 2022. Genetic testing was based on a targeted-sequencing panel of 22 MMAF-related genes. Morphological, ultrastructural, and immunostaining analyses were conducted in 2022. We also performed assisted reproductive technology (ART) with ICSI to explore the treatment strategies. Participants/materials, setting, methods Peripheral blood and semen samples were collected from every participant. The CFAP69 variant was identified by genetic testing with targeted-panel sequencing of 22 MMAF-associated genes and validated through Sanger sequencing, pedigree analysis and in silico analysis. Papanicolaou staining, SEM, immunofluorescence, and TEM were performed to explore the effect of the variant. ICSI was carried out for the affected couples to get their own progenies. Main results and the role of chance We identified a novel frameshift variant in CFAP69 (c.2061dup, p. Pro688Thrfs*5) from a MMAF-affected infertile male with low sperm motility and malformed morphology of sperm. Furthermore, immunofluorescence staining, and transmission electronic microscopy revealed that the variant induced reduction of CFAP69 expression and the aberrant ultrastructure including the absence of the central pair and disorder of the microtubule doublets in the patient’s spermatozoa. Moreover, the partner of the proband was able to conceive through ICSI and birthed a healthy girl. Limitations, reasons for caution A limitation of this study is the low number of variants identified in CFAP69 and the small number of CFAP69-mutant patients available. Additional CFAP69 variants and cases are needed to better characterize the genetic etiology of the MMAF phenotype and to improve the management of MMAF patients with CFAP69 variants. Wider implications of the findings This study extended the mutant spectrum of the CFAP69 gene and could facilitate researchers and clinicians to understand the genetic etiology of MMAF better, thus improving counseling of infertile men with MMAF in the future. Trial registration number not applicable

O-253 Novel biallelic variants in DNAH1 cause multiple morphological abnormalities of sperm flagella with favorable outcomes of fertility after ICSI in Han Chinese males

Abstract Study question Is there any novel variants and mutant hotspot in DNAH1 gene related to multiple morphological abnormalities of sperm flagella (MMAF) and male infertility in humans? Summary answer We identified eighteen variants of DNAH1 gene in eleven MMAF-affected Chinese men, including fourteen novel variants, four previously reported variants, and a candidate mutant hotspot. What is known already As a specific type of asthenoteratozoospermia, MMAF is characterized by composite flagellar defects including absent, short, coiled, angulation, and irregular-caliber, and usually presents ultrastructural abnormalities of axonemal and peri-axonemal structures. Genetic defects are the major cause of MMAF and biallelic variants of DNAH1 have been found to account for approximately 30% of studied human MMAF cohorts. Males with DNAH1 variants usually present with primary infertility owing to abnormal sperm morphology and motility. Intracytoplasmic sperm injection (ICSI) is the main strategy applied for patients with DNAH1 variants to conceive. Study design, size, duration A total of thirty-five patients with MMAF phenotype were recruited from the center for reproductive medicine from August 2019 to June 2022. A next-generation sequencing (NGS) panel of 22 MMAF-related genes was applied for genetic testing and the hereditary pattern was confirmed with Sanger sequencing. Sperm morphological analysis, immunostaining assays, and assisted reproductive therapy were performed in 2021 and 2022. Participants/materials, setting, methods The DNAH1 variants were identified by NGS and confirmed by Sanger sequencing. Pedigree analysis and in silico analysis further confirmed the pathogenicity or likely pathogenicity of these variants. Papanicolaou-staining, scanning and transmission electronic microscopy, and immunostaining were used to characterize the morphology and ultrastructure of spermatozoa. ICSI was applied for the assisted reproductive therapy of DNAH1-mutant patients and the outcomes of fertilization, embryo cleavage, and delivery were analyzed. Main results and the role of chance We totally identified 18 different DNAH1 variants (NM_015512.5) in 11 of 35 MMAF-affected males, including 9 missense variants (c.7690G>A, p.A2564T; c.10970C>G, p.T3657R; c.5584G>A, p.G1862R; c.6887T>C, p.L2296P; c.12122C>T, p.T4041I; c.1832T>C, p.L611P; c.2738C>A, p.A913D; c.5795G>A, p.R1932Q; c.7066C>T, p.R2356W) and 9 loss-of-function variants (c.11726_11727delCT, p.P3909Rfs*33; c.12172C>T, p.Q4058*; c.5104C>T, p.R1702*; c.12210del, p.V4071Cfs*54; c.8533del, p.D2845Mfs*2; c.12178_12190del, p.E4060Pfs*61; c.2301-1G>T; c.4552C>T, p.Q1518*; c.12118_12119delCA, p.Q4040Dfs*33). Moreover, 77.8% (14/18) of the identified variants were novel. The results of Papanicolaou-staining, scanning electronic microscopy, and immunofluorescence demonstrated the typical characteristics of MMAF, consisting of absent, short, coiled, angulation, and irregular-caliber flagella, of the spermatozoa affected by DNAH1 variants. Transmission electronic microscopy further revealed the compound changes of flagella ultrastructure, including loss of central pair and disorganization of microtubule doublets and outer dense fibers. Six of eleven underwent assisted reproductive therapy with ICSI in our clinic. The rates of fertilization, usable embryos and clinical pregnancy for patients with DNAH1 variants following ICSI were 81.5%, 52.8% and 66.7%, respectively. To date, three couples have given birth to a total of five healthy children. Limitations, reasons for caution Because of distance and inconvenience, five of the eleven DNAH1-affected men didn’t provide additional semen samples for functional analysis. In addition, as the absence of specific antibody of DNAH1, immunostaining for DNAH1 was not performed in this study. Wider implications of the findings This study significantly expands the variant spectrum of DNAH1 gene related to MMAF and male infertility in humans. The systematic description of assisted reproduction therapies will provide clinicians with new insights into molecular diagnosis and genetic counseling. Trial registration number not applicable

Novel biallelic variants in DNAH1 cause multiple morphological abnormalities of sperm flagella with favorable outcomes of fertility after ICSI in Han Chinese males.

Multiple morphological abnormalities of sperm flagella is an idiopathic asthenoteratozoospermia characterized by absent, short, coiled, angulation, and irregular-caliber flagella. Genetic variants of DNAH1 gene have been identified as a causative factor of multiple morphological abnormalities of sperm flagella and intracytoplasmic sperm injection is an available strategy for infertile males with dynein axonemal heavy chain 1 defects to conceive. To identify novel variants and candidate mutant hotspots of DNAH1 gene related to multiple morphological abnormalities of sperm flagella and male infertility in humans. TheDNAH1variants were identified by whole exome sequencing and confirmed with Sanger sequencing. Papanicolaou staining, scanning and transmission electron microscopy, and immunostaining were performed to investigate the morphological and ultrastructural characteristics of spermatozoa. Intracytoplasmic sperm injection was applied for the assisted reproductive therapy of males harboring biallelic DNAH1 variants. We identified 18 different DNAH1 variants in 11 unrelated families, including nine missense variants (p.A2564T, p.T3657R, p.G1862R, p.L2296P, p.T4041I, p.L611P, p.A913D, p.R1932Q, p.R2356W) and nine loss-of-function variants (c.2301-1G>T, p.Q1518*, p.R1702*, p.D2845Mfs*2, p.P3909Rfs*33, p.Q4040Dfs*33, p.Q4058*, p.E4060Pfs*61, p.V4071Cfs*54). A total of 66.7% (12/18) of the identified variants were novel. Morphological analysis based on Papanicolaou staining and scanning electron microscopy demonstrated the typical multiple morphological abnormalities of sperm flagella characteristics of dynein axonemal heavy chain 1-deficient spermatozoa. Immunostaining further revealed the absence of inner dynein arms but not outer dynein arms, which induced a general ultrastructural disorganization, such as the loss of central pair and mis-localization of the microtubule doublets and outer dense fibers. To date, seven affected couples have accepted the intracytoplasmic sperm injection treatment, and three of them have given birth to five healthy babies. These findings further expand the variant spectrum of DNAH1 gene related to multiple morphological abnormalities of sperm flagella and male infertility in humans, thus providing new information for the molecular diagnosis of asthenoteratozoospermia. The favorable fertility outcomes of intracytoplasmic sperm injection will facilitate the genetic counseling and clinical treatment of infertile males with multiple morphological abnormalities of sperm flagella in the future.

Absence of CEP78 causes photoreceptor and sperm flagella impairments in mice and a human individual.

Cone-rod dystrophy (CRD) is a genetically inherited retinal disease that can be associated with male infertility, while the specific genetic mechanisms are not well known. Here, we report CEP78 as a causative gene of a particular syndrome including CRD and male infertility with multiple morphological abnormalities of sperm flagella (MMAF) both in human and mouse. Cep78 knockout mice exhibited impaired function and morphology of photoreceptors, typified by reduced ERG amplitudes, disrupted translocation of cone arrestin, attenuated and disorganized photoreceptor outer segments (OS) disks and widen OS bases, as well as interrupted connecting cilia elongation and abnormal structures. Cep78 deletion also caused male infertility and MMAF, with disordered '9+2' structure and triplet microtubules in sperm flagella. Intraflagellar transport (IFT) proteins IFT20 and TTC21A are identified as interacting proteins of CEP78. Furthermore, CEP78 regulated the interaction, stability, and centriolar localization of its interacting protein. Insufficiency of CEP78 or its interacting protein causes abnormal centriole elongation and cilia shortening. Absence of CEP78 protein in human caused similar phenotypes in vision and MMAF as Cep78-/- mice. Collectively, our study supports the important roles of CEP78 defects in centriole and ciliary dysfunctions and molecular pathogenesis of such multi-system syndrome.

Compound Heterozygous Mutations in FSIP2 Cause Morphological Abnormalities in Sperm Flagella Leading to Male Infertility

Multiple morphological abnormalities of sperm flagella (MMAF) indicate severe teratozoospermia. The fibrous sheath interacting protein 2 (FSIP2) plays an important role in the normal construction of the flagella. In this study, a novel compound heterozygous mutation site of FSIP2, involving c.272_275delinsAGGTTTTTATA (p.L92Vfster74) and c.16788_16791del (p.E5596fs), was identified using whole-exome sequencing in a 32-year-old male. Electron microscope images revealed thick sperm neck, scattered sperm mitochondria, and short sperm tail. In addition, FSIP2 could not be visualized in sperm cells via immunofluorescence staining. Moreover, we used a protein domain prediction tool to identify a potential FSIP2 functional domain (5901-6774), the corresponding deletion of which was responsible for the MMAF phenotype in the infertile man. Finally, we reviewed the literature on FSIP2 and found that FSIP2 mutations are relatively concentrated, with high-frequency mutation regions in exon 16 and exon 17 accounting for 50% (10/20) and 35% (7/20) of cases, respectively. In conclusion, FISP2 is a common pathogenic gene of MMAF, which may provide a rationale for genetic counseling in the next generation of patients with male infertility.

Clinical detection, diagnosis and treatment of morphological abnormalities of sperm flagella: A review of literature.

Sperm carries male genetic information, and flagella help move the sperm to reach oocytes. When the ultrastructure of the flagella is abnormal, the sperm is unable to reach the oocyte and achieve insemination. Multiple morphological abnormalities of sperm flagella (MMAF) is a relatively rare idiopathic condition that is mainly characterized by multiple defects in sperm flagella. In the last decade, with the development of high-throughput DNA sequencing approaches, many genes have been revealed to be related to MMAF. However, the differences in sperm phenotypes and reproductive outcomes in many cases are attributed to different pathogenic genes or different pathogenic mutations in the same gene. Here, we will review information about the various phenotypes resulting from different pathogenic genes, including sperm ultrastructure and encoding proteins with their location and functions as well as assisted reproductive technology (ART) outcomes. We will share our clinical detection and diagnosis experience to provide additional clinical views and broaden the understanding of this disease.

P-524 Bi-allelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia

Abstract Study question Are mutations in cilia and flagella-associated protein 61 (CFAP61) associated with human male infertility? Summary answer Bi-allelic variants ([NM_015585.4: c.1654C>T (p.R552C) and c.2911G>A (p.D971N), c.144-2A>G and c.1666G>A (p.G556R)] in CFAP61 were identified as contributory genetics factor in severe oligoasthenoteratozoospermia (OAT). What is known already Cfap61 knockout mice were infertile due to multiple morphological abnormalities of the sperm flagella (MMAF). However, so far there is no direct evidence that mutations of CFAP61 cause OAT and male infertility. Study design, size, duration Variant screening was performed by whole-exome sequencing (WES) from 325 infertile patients with OAT and 392 fertile individuals. A knockout mouse model was generate to confirm the candidate disease-causing gene, intracytoplasmic sperm injection (ICSI) was used to evaluate the efficiency of clinical treatment. Participants/materials, setting, methods A total 325 OAT-affected patients and 392 men with normal fertility were recruited from China. WES was performed, followed by Sanger sequencing validation. In silico bioinformatics predictions and in vitro functional analyses were performed to evaluate the impacts of candidate disease-causing variants. Hematoxylin and eosin (H&E) staining, electron microscopy, and immunofluorescence assays were performed to evaluate the sperm morphology. Two OAT-affected men with CFAP61 variants were treated by ICSI, and pregnancy outcomes were followed. Main results and the role of chance We identified bi-allelic CFAP61 variants [NM_015585.4: c.1654C>T (p.R552C) and c.2911G>A (p.D971N), c.144-2A>G and c.1666G>A (p.G556R)] in two (0.62%) of the 325 OAT-affected men. In silico bioinformatics analysis predicted that all four variants were deleterious, and in vitro functional analysis confirmed the deleterious effects of the mutants. Notably, H&E staining and electron microscopy analyses of the spermatozoa revealed multiple morphological abnormalities of sperm flagella, the absence of central pair microtubules, and mitochondrial sheath malformation in sperm flagella from man with CFAP61 variants. Further immunofluorescence assays revealed markedly reduced CFAP61 staining in the sperm flagella. In addition, Cfap61-deficient mice showed the OAT phenotype, suggesting that loss of function of CFAP61 was the cause of OAT. Two individuals accepted ICSI therapy using their own ejaculated sperm, and one of them succeeded in fathering a healthy baby. Limitations, reasons for caution Limitations include the lack of in vivo data from the one of patients, and the exact molecular mechanism should be further investigated. Wider implications of the findings Our findings indicate that CFAP61 is essential for spermatogenesis and that bi-allelic CFAP61 variants lead to OAT and male infertility in humans and mice. In addition, our results show that ICSI treatment can be recommended for CFAP61-related OAT. Trial registration number not applicable

Loss of function mutation in DNAH7 induces male infertility associated with abnormalities of the sperm flagella and mitochondria in human.

Male infertility is an increasingly serious health problem affecting couples of reproductive age. Mutations in axoneme-associated genes cause male infertility. Dynein arm proteins are essential in sustaining normal axonemes and promote flagellar motility. However, the function of DNAH7 in male fertility in vivo remains unclear. Herein, we showed that DNAH7 disruption in humans results in male infertility, which was characterised by multiple morphological abnormalities of sperm flagella. The axoneme structure of the sperm from a DNAH7-deficient patient revealed the loss of inner dynein arms. Moreover, the mitochondria of the sperm flagella detached and dispersed outside the axoneme, leading to abnormalities in the mitochondrial sheath in the mid-piece region. Live birth was achieved via intracytoplasmic sperm injection. Thus, DNAH7 is critical for axoneme and mitochondrial development in human sperm. These findings further clarify the spectrum of DNAH7 biology and provide new insights for diagnosing infertility and treating patients harbouring DNAH7 mutations.

Patient with multiple morphological abnormalities of sperm flagella caused by a novel ARMC2 mutation has a favorable pregnancy outcome from intracytoplasmic sperm injection.

To investigate the potential genetic cause in a primary infertility patient with multiple morphological abnormalities of sperm flagella (MMAF). The patient's sperm was observed by light and electron microscopy. Whole-exome sequencing (WES) was carried out to identify candidate genes. Then, the mutation found by WES was verified by Sanger sequencing. The proteins interacting with ARMC2 were revealed by co-immunoprecipitation (co-IP) and mass spectrometry. Intracytoplasmic sperm injection (ICSI) was carried out to achieve successful pregnancy. Typical MMAF phenotype (absent, short, coiled, bent irregular flagella) was shown in the patient's sperm. A novel homozygous mutation in ARMC2 (c.1264C > T) was identified. The proteins interacting with ARMC2 we found were CEP78, PGAM5, RHOA, FXR1, and SKIV2L2. The ICSI therapy was successful, and boy-girl twins were given birth. We found a novel mutation in ARMC2 which led to MMAF and male infertility. This is the first report of ICSI outcome of patient harboring ARMC2 mutation. The interacting proteins indicated that ARMC2 might be involved in multiple processes of spermatogenesis.

Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia

BackgroundThe genetic causes for most male infertility due to severe oligoasthenoteratozoospermia (OAT) remain unclear.ObjectiveTo identify the genetic cause of male infertility characterised by OAT.MethodsVariant screening was performed by whole-exome sequencing...

Successful Results of Intracytoplasmic Sperm Injection of a Chinese Patient With Multiple Morphological Abnormalities of Sperm Flagella Caused by a Novel Splicing Mutation in CFAP251

Asthenospermia is one of the most important causes of male infertility. Among asthenospermia, multiple morphological abnormalities of sperm flagella (MMAF) are relatively rare idiopathic conditions characterized by multiple defects in sperm flagella. Although many studies focusing on the genetic factors of MMAF have been conducted, its pathogenesis and treatment effect remain largely unknown. Here, we report a male patient from a nonconsanguineous Chinese family who exhibited a typical MMAF phenotype revealed by morphological analysis. We identified splicing mutations in CFAP251 (c.1192-3C>G), and the mutation was proven to cause exon skipping. In addition, western blotting and immunofluorescence analysis of the spermatozoa from the proband and a control subject revealed a significantly lower expression of CFAP251 protein due to pathogenic mutation. Interestingly, the patient’s mother was a heterozygous carrier for the mutation, but his father was not, and finally, the inheritance pattern was proven to be maternal uniparental disomy. We applied an intracytoplasmic sperm injection and achieved a successful pregnancy. Above all, our findings expand the spectrum of CFAP251 pathogenic mutations and provide more indications for clinical genetic counseling and assisted reproductive treatment for such patients.

Novel Loss-of-Function Mutations in DNAH1 Displayed Different Phenotypic Spectrum in Humans and Mice.

Male infertility is a prevalent disorder distressing an estimated 70 million people worldwide. Despite continued progress in understanding the causes of male infertility, idiopathic sperm abnormalities such as multiple morphological abnormalities of sperm flagella (MMAF) still account for about 30% of male infertility. Recurrent mutations in DNAH1 have been reported to cause MMAF in various populations, but the underlying mechanism is still poorly explored. This study investigated the MMAF phenotype of two extended consanguineous Pakistani families without manifesting primary ciliary dyskinesia symptoms. The transmission electron microscopy analysis of cross-sections of microtubule doublets revealed a missing central singlet of microtubules and a disorganized fibrous sheath. SPAG6 staining, a marker generally used to check the integration of microtubules of central pair, further confirmed the disruption of central pair in the spermatozoa of patients. Thus, whole-exome sequencing (WES) was performed, and WES analysis identified two novel mutations in the DNAH1 gene that were recessively co-segregating with MMAF phenotype in both families. To mechanistically study the impact of identified mutation, we generated Dnah1 mice models to confirm the in vivo effects of identified mutations. Though Dnah1 △iso1/△iso1 mutant mice represented MMAF phenotype, no significant defects were observed in the ultrastructure of mutant mice spermatozoa. Interestingly, we found DNAH1 isoform2 in Dnah1 △iso1/△iso1 mutant mice that may be mediating the formation of normal ultrastructure in the absence of full-length protein. Altogether we are first reporting the possible explanation of inconsistency between mouse and human DNAH1 mutant phenotypes, which will pave the way for further understanding of the underlying pathophysiological mechanism of MMAF.

Novel frameshift mutation in STK33 is associated with asthenozoospermia and multiple morphological abnormalities of the flagella.

Serine/threonine kinases domain-containing proteins are known to play important functions in sperm flagella and male fertility. However, the roles of these proteins in human reproduction remain poorly understood and whether their variants are associated with human asthenozoospermia have not been reported. Here, we recruited a Pakistani family having four infertile patients diagnosed with idiopathic asthenozoospermia without any ciliary-related symptoms. Whole-exome sequencing identified a novel homozygous frameshift mutation (c.1235del, p.T412Kfs*14) in serine/threonine kinase 33 (STK33), which displays a highly conserved and predominant expression in testis in humans. This variant led to a dramatic reduction of STK33 messenger RNA (mRNA) in the patients. Patients homozygous for the STK33 variant presented reduced sperm motility, frequent morphological abnormalities of sperm flagella and completely disorganized flagellar ultrastructures, which are typical for multiple morphological abnormalities of the flagella (MMAF) phenotypes. Overall, these findings present evidence establishing that STK33 is an MMAF-related gene and provide new insights for understanding the role of serine/threonine kinases domain-containing proteins in human male reproduction.

Mutations in DNAH8 contribute to multiple morphological abnormalities of sperm flagella and male infertility.

Asthenoteratospermia is an important cause of male infertility. Here, we report two infertile patients with severe asthenoteratospermia accompanied by new genetic abnormality. Whole-exome sequencing and bioinformatics analysis suggested that compound heterozygous mutations in DNAH8 (MIM:603337) may be responsible for multiple morphological abnormalities of the sperm flagella (MMAF). Immunofluorescence assay showed that DNAH8 protein expression was significantly decreased in the sperm tail of the patients, and electron microscopy exhibited an abnormal flagellum ultrastructure, while clinical pregnancy could be achieved by intracytoplasmic sperm injection. Therefore, the compound heterozygous mutations in the DNAH8 gene may be responsible for MMAF.

Advance in genetic research on multiple morphological abnormalities of sperm flagellum

Multiple morphological abnormalities of sperm flagella (MMAF) is a type of teratospermia caused by genetic defects. The sperm motility is low due to absence of flagella, shortness, curling, bending or irregularity of sperms, and combination of various abnormalities. Ultrastructure may show flagellum assembly abnormalities, which are mainly manifested by the absence of microtubules in the axoneme and defects of various structures such as fibrous sheath, outer dense fiber, mitochondrial sheath and dynein arms. MMAF males are unable to reproduce naturally and require assisted reproductive technology to obtain offsprings. For the heterogeneity of molecular etiology of MMAF, the outcome of assisted reproduction may be different. Here the candidate genes of MMAF and their functional mechanisms are summarized, which may provide a reference for clinical diagnosis, treatment and research for this disorder.

DNAH17 is associated with asthenozoospermia and multiple morphological abnormalities of sperm flagella.

Multiple morphological abnormalities of the sperm flagella (MMAF) is one kind of severe asthenozoospermia, which is caused by dysplastic development of sperm flagella. In our study, we sought to investigate the novel gene mutations leading to severe asthenozoospermia and MMAF. The patient's spermatozoa were tested by Papanicolaou staining and transmission electron microscopy. Whole exome sequencing was performed on the patient with severe asthenozoospermia and MMAF. Sanger sequencing verified the mutations in the family. The expression of DNAH17 was detected by immunofluorescence and Western blot. Spermatozoa sample from the patient showed severe asthenozoospermia and MMAF. We detected biallelic mutations (c.C4445T, p.A1482V and c.C6857T, and p.S2286L) in DNAH17 (MIM:610063). The protein expression of DNAH17 was almost undetectable in spermatozoa from the patient with the biallelic mutations. These results demonstrated that DNAH17 may be involved in severe asthenozoospermia and MMAF.

Insight on multiple morphological abnormalities of sperm flagella in male infertility: what is new?

The syndrome of multiple morphological abnormalities of the sperm flagella (MMAF) is a specific kind of asthenoteratozoospermia with a mosaic of flagellar morphological abnormalities (absent, short, bent, coiled, and irregular flagella). MMAF was proposed in 2014 and has attracted increasing attention; however, it has not been clearly understood. In this review, we elucidate the definition of MMAF from a systematical view, the difference between MMAF and other conditions with asthenoteratozoospermia or asthenozoospermia (such as primary mitochondrial sheath defects and primary ciliary dyskinesia), the knowledge regarding its etiological mechanism and related genetic findings, and the clinical significance of MMAF for intracytoplasmic sperm injection and genetic counseling. This review provides the basic knowledge for MMAF and puts forward some suggestions for further investigations.