A <i>DNAH17</i> missense variant causes flagella destabilization and asthenozoospermia

Zhang, Beibei; Ma, Hui; Khan, Teka; Ma, Ao; Li, Tao; Zhang, Huan; Gao, Jianing; Zhou, Jianteng; Li, Yang; Yu, Chang-Ping; Bao, Jianqiang; Ali, Asim; Murtaza, Ghulam; Yin, Hong; Gao, Qian; Jiang, Xiaohua; Zhang, Feng; Liu, Chunyu; Khan, Ihsan; Zubair, Muhammad; Hussain, Hafiz Muhammad Jafar; Khan, Ranjha; Yousaf, Ayesha; Yuan, L.; Lu, Yan; Xu, Xiaoling; Wang, Yun; Tao, Qizhao; Hao, Qiaomei; Fang, Hui; Cheng, Hui‐Ming; Zhang, Yuanwei; Shi, Qinghua

doi:10.1084/jem.20182365

Cited by 97 publications

(104 citation statements)

References 65 publications

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“…the deletion of Ttll9 in mice caused doublet 7 shortening in the distal portion of the principal piece in sperm flagellum, along with reduction of doublet 5 polyglutamylation, leading to biased anti-hook bending and male infertility, similar to Cfap97d1 knockout males [45]. Similarly, deletion of Vdac3 [44], Pla2g3 [46], and DNAH17 [47] caused instability of sperm microtubule doublets 4-7, associated with sperm motility defects and male infertility. Additionally, in a DNAH17 missense variant, spermatozoa were disorganized during storage in cauda epididymis but not in testes, consistent with our studies.…”

Section: Plos Geneticsmentioning

confidence: 99%

“…Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare syndrome that causes primary infertility. So far there are several genes associated with MMAF: CFAP43, CFAP44, CFAP69, AKAP4, DNAH1, DNAH17, CCDC39, and QRICH2 [47,[51][52][53][54][55][56]. However, the genetic causes are unknown in approximately half of MMAF cases.…”

Section: Plos Geneticsmentioning

confidence: 99%

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Cfap97d1 is important for flagellar axoneme maintenance and male mouse fertility

et al. 2020

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The flagellum is essential for sperm motility and fertilization in vivo. The axoneme is the main component of the flagella, extending through its entire length. An axoneme is comprised of two central microtubules surrounded by nine doublets, the nexin-dynein regulatory complex, radial spokes, and dynein arms. Failure to properly assemble components of the axoneme in a sperm flagellum, leads to fertility alterations. To understand this process in detail, we have defined the function of an uncharacterized gene, Cfap97 domain containing 1 (Cfap97d1). This gene is evolutionarily conserved in mammals and multiple other species, including Chlamydomonas. We have used two independently generated Cfap97d1 knockout mouse models to study the gene function in vivo. Cfap97d1 is exclusively expressed in testes starting from post-natal day 20 and continuing throughout adulthood. Deletion of the Cfap97d1 gene in both mouse models leads to sperm motility defects (asthenozoospermia) and male subfertility. In vitro fertilization (IVF) of cumulus-intact oocytes with Cfap97d1 deficient sperm yielded few embryos whereas IVF with zona pellucida-free oocytes resulted in embryo numbers comparable to that of the control. Knockout spermatozoa showed abnormal motility characterized by frequent stalling in the anti-hook position. Uniquely, Cfap97d1 loss caused a phenotype associated with axonemal doublet heterogeneity linked with frequent loss of the fourth doublet in the sperm stored in the epididymis. This study demonstrates that Cfap97d1 is required for sperm flagellum ultra-structure maintenance, thereby playing a critical role in sperm function and male fertility in mice.

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Section: Plos Geneticsmentioning

confidence: 99%

Section: Plos Geneticsmentioning

confidence: 99%

Cfap97d1 is important for flagellar axoneme maintenance and male mouse fertility

et al. 2020

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“…DNAH17 encodes an outer dynein arm protein and is specifically detected in testes and sperm, but not in cilia or ciliary tissues. 13,14 Biallelic variants in DNAH17 have been associated with asthenozoospermia, but it appears that different types of DNAH17 variants are implicated in different sperm phenotypes. In two recent studies, biallelic DNAH17 variants that led to the loss of DNAH17 proteins were identified in patients with MMAF.…”

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confidence: 99%

“…14,15 Whereas, we also characterized a DNAH17 missense variant in a consanguineous family exhibiting reduced sperm motility but normal sperm morphology, the mutant DNAH17 protein remained present in flagella, and this variant specifically caused frequent missing of MTD(s) 4-7 in flagella resulting from storage of sperm in epididymis. 13 Hence, the role of DNAH17 in human asthenozoospermia and the pathogenesis of its variants need to be further investigated.…”

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confidence: 99%

Novel loss‐of‐function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice

et al. 2020

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Multiple morphological abnormalities of the flagella (MMAF) is a genetically heterogeneous disorder leading to male infertility. Recent studies have revealed that DNAH17 variants are associated with MMAF, yet there is no functional evidence in support of their pathnogenicity. Here, we recruited two consanguineous families of Pakistani and Chinese origins, respectively, diagnosed with MMAF. Whole-exome sequencing identified novel homozygous DNAH17 variants, which led to loss of DNAH17 proteins, in the patients. Transmission electron microscope analyses revealed completely disorganized axonemal structure as the predominant anomaly and increased frequencies of missings of microtubule doublet(s) 4-7 in sperm flagella of patients. Similar to those found in patients, Dnah17 −/− mice also displayed MMAF phenotype along with completely disorganized axonemal structures. Clusters of disorganized microtubules and outer dense fibers were observed in developing spermatids, indicating impaired sperm flagellar assembly. Besides, we also noticed many elongating spermatids with a deformed nuclear shape and abnormal step 16 spermatids that failed to spermiate, which subsequently underwent apoptosis in Dnah17-null mice. These findings present direct evidence establishing that DNAH17 is a MMAF-related gene in humans Beibei Zhang, Ihsan Khan, and Chunyu Liu contributed equally to this work.

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“…Idiopathic asthenospermia (IAS) falls into this category but has an unknown etiology. IAS males have normal sperm parameters except for low sperm motility 1,2 . Karyotype analysis is an important technique for chromosome examination and genetic background screening.…”

Section: Hypomethylation Of the Daz3 Promoter In Idiopathic Asthenospmentioning

confidence: 99%

Hypomethylation of the DAZ3 promoter in idiopathic asthenospermia: a screening tool for liquid biopsy

Zhang

et al. 2020

Sci Rep

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Given the role of the deleted in azoospermia gene in male infertility, whether the somatic deleted in azoospermia methylation status is associated with idiopathic asthenospermia should be determined. To investigate the methylation levels of the deleted in azoospermia promoter in peripheral white blood cells from idiopathic asthenospermia patients relative to those in normozoospermia controls, 61 ethylene diamine tetraacetic acid anticoagulant blood samples were drawn from all participants for DNA isolation. The deleted in azoospermia promoter methylation ratio was detected by MassARRAY-based methylation quantification and confirmed by quantitative methylation-specific polymerase chain reaction. A MassARRAY-based methylation analysis showed that the deleted in azoospermia 3 promoter (0 to − 2 kbp) was significantly hypomethylated in peripheral white blood cells from idiopathic asthenospermia males, specifically one CpG site (− 246 to − 247). Quantitative methylation-specific polymerase chain reaction data further confirmed that the methylation level of the deleted in azoospermia 3 promoter region in idiopathic asthenospermia patients was significantly lower than that in normozoospermia males. The area under the receiver operating characteristic curve determined by quantitative methylation-specific polymerase chain reaction was 0.737 (95% confidence interval: 0.552 to 0.924), with a sensitivity of 53.9% and a specificity of 88.2% at a cut-off level of 74.7%. Therefore, our results suggested that methylation ratio detection of the deleted in azoospermia 3 promoter region by real-time polymerase chain reaction assay is a promising and feasible tool for liquid biopsy in the clinical laboratories. The methylation status of other reported infertility-related genes should also be investigated in peripheral white blood cells.

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A DNAH17 missense variant causes flagella destabilization and asthenozoospermia

Cited by 97 publications

References 65 publications

Cfap97d1 is important for flagellar axoneme maintenance and male mouse fertility

Cfap97d1 is important for flagellar axoneme maintenance and male mouse fertility

Novel loss‐of‐function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice

Hypomethylation of the DAZ3 promoter in idiopathic asthenospermia: a screening tool for liquid biopsy

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