Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype

Sha, Yanwei; Liu, Wensheng; Wei, Xiaoli; Zhu, Xingshen; Luo, Xiangmin; Liang, Lin; Guo, Tong

doi:10.1111/cge.13602

Cited by 31 publications

(19 citation statements)

References 29 publications

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“…MMAF is an autosomal‐recessive disorder linked to mutations in several genes, including DNAH1 (Ben Khelifa et al., ; Wang et al., ), DNAH2 (Li et al., ), CFAP43 , and CFAP44 (Sha et al., ; Tang et al., ; Wu et al., ), CFAP69 (Dong et al., ; He et al., ), CFAP251 (also known as WDR66 ) (Kherraf et al., ; Li et al., ), FSIP2 (Martinez et al., ), ARMC2 (Coutton et al., ), AK7 ( Lores et al., ), QRICH2 (Shen et al., ), SPEF2 (Liu et al., ; Sha et al., ), TTC21A (Liu et al., ), and CEP135 (Sha et al., ). However, further research is needed to determine the genetic causes of the remaining 40%–50% of the MMAF patients (Liu et al., ).…”

Section: Introductionmentioning

confidence: 99%

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

Sha

Wei

Ding

et al. 2019

Annals of Human Genetics

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Background 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. Methods and Materials 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. Results 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. Conclusion These results demonstrated that DNAH17 may be involved in severe asthenozoospermia and MMAF.

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Section: Introductionmentioning

confidence: 99%

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

Sha

Wei

Ding

et al. 2019

Annals of Human Genetics

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“…Variations in CFAP69 were also found in infertile men who exhibited severe flagellar abnormalities, including flagella being short, coiled, absent, and of irregular caliber, which is referred to as multiple morphological abnormalities of the flagella (MMAF) [ 12 , 17 ]. Variations in another CP component, SPEF2, were found in MMAF patients as well [ 29 , 30 , 52 , 63 ], suggesting that CP components are important for sperm flagellar formation not only in mice but also humans.…”

Section: Ko Mouse Lines That Do Not Exhibit Premature Lethalitymentioning

confidence: 99%

Analysis of the sperm flagellar axoneme using gene-modified mice

2020

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Infertility is a global health issue that affects 1 in 6 couples, with male factors contributing to 50% of cases. The flagellar axoneme is a motility apparatus of spermatozoa, and disruption of its structure or function could lead to male infertility. The axoneme consists of a “9+2” structure that contains a central pair of two singlet microtubules surrounded by nine doublet microtubules, in addition to several macromolecular complexes such as dynein arms, radial spokes, and nexin-dynein regulatory complexes. Molecular components of the flagellar axoneme are evolutionally conserved from unicellular flagellates to mammals, including mice. Although knockout (KO) mice have been generated to understand their function in the formation and motility regulation of sperm flagella, the majority of KO mice die before sexual maturation due to impaired ciliary motility, which makes it challenging to analyze mature spermatozoa. In this review, we introduce methods that have been used to overcome premature lethality, focusing on KO mouse lines of central pair components.

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“…There are two evolutionarily conserved bidirectional transport platforms that are involved in sperm flagellum biogenesis, including intramanchette transport (IMT) and intraflagellar transport (IFT) (Kierszenbaum, 2001(Kierszenbaum, , 2002San Agustin et al, 2015). IMT and IFT share similar cytoskeletal components, namely microtubules and F-actin, that provide tracks for the transport of structural proteins to the developing tail (Kierszenbaum et al, 2011a), and mutations in TTC21A, TTC29, SPEF2, and CFAP69, which have been reported to disrupt sperm flagellar protein transport, also lead to MMAF (Dong et al, 2018;Liu C. et al, 2019;Sha et al, 2019;Liu et al, 2020a).…”

Section: Introductionmentioning

confidence: 99%

Essential Role of CFAP53 in Sperm Flagellum Biogenesis

Liu

et al. 2021

Front. Cell Dev. Biol.

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The sperm flagellum is essential for male fertility. Despite vigorous research progress toward understanding the pathogenesis of flagellum-related diseases, much remains unknown about the mechanisms underlying the flagellum biogenesis itself. Here, we show that the cilia and flagella associated protein 53 (Cfap53) gene is predominantly expressed in testes, and it is essential for sperm flagellum biogenesis. The knockout of this gene resulted in complete infertility in male mice but not in the females. CFAP53 localized to the manchette and sperm tail during spermiogenesis, the knockout of this gene impaired flagellum biogenesis. Furthermore, we identified two manchette and sperm tail-associated proteins that interacted with CFAP53 during spermiogenesis. Together, our results suggest that CFAP53 is an essential protein for sperm flagellum biogenesis, and its mutations might be associated with multiple morphological abnormalities of the flagella (MMAF).

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Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype

Cited by 31 publications

References 29 publications

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

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

Analysis of the sperm flagellar axoneme using gene-modified mice

Essential Role of CFAP53 in Sperm Flagellum Biogenesis

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