Bi-allelic mutations of DNAH10 cause primary male infertility with asthenoteratozoospermia in humans and mice

Tu, Chaofeng; Cong, Jiangshan; Zhang, Qianjun; He, Xiaojin; Zheng, Rui; Yang, Xiaoxuan; Gao, Yang; Wu, Huan; Lv, Mingrong; Gu, Yayun; Lü, Shan; Liu, Chunyu; Tian, Shixiong; Meng, Lanlan; Wang, Weili; Tan, Chen; Nie, Hongchuan; Li, Dongyan; Zhang, Huan; Gong, Fei; Hu, Liang; Lu, Guangxiu; Xu, Wei; Lin, Ge; Zhang, Feng; Cao, Yunxia; Tan, Yue‐Qiu

doi:10.1016/j.ajhg.2021.06.010

Cited by 57 publications

(39 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, bi‐allelic mutation of DNAH10 (an IDA heavy chain) induces male infertility with multiple morphological abnormalities in the flagella (MMAF), but the infertile patients do not exhibit PCD symptoms, such as lung disease, sinusitis, and situs inversus . 100 Similar results have been obtained in mutation or deletion of DNAH1, 101 , 102 DNAH2, 103 DNAH8, 104 and DNAH17. 105 , 106 These gene mutations cause sperm abnormalities such as short or coiled‐tail, disorganized axoneme, and decreased motility but do not exhibit other obviously clinical PCD manifestations.…”

Section: Proteins Compose the Axonemal Structuresupporting

confidence: 73%

Molecular basis of the morphogenesis of sperm head and tail in mice

Yogo

2022

Reprod Medicine & Biology

View full text Add to dashboard Cite

Background The spermatozoon has a complex molecular apparatus necessary for fertilization in its head and flagellum. Recently, numerous genes that are needed to construct the molecular apparatus of spermatozoa have been identified through the analysis of genetically modified mice. Methods Based on the literature information, the molecular basis of the morphogenesis of sperm heads and flagella in mice was summarized. Main findings (Results) The molecular mechanisms of vesicular trafficking and intraflagellar transport in acrosome and flagellum formation were listed. With the development of cryo‐electron tomography and mass spectrometry techniques, the details of the axonemal structure are becoming clearer. The fine structure and the proteins needed to form the central apparatus, outer and inner dynein arms, nexin‐dynein regulatory complex, and radial spokes were described. The important components of the formation of the mitochondrial sheath, fibrous sheath, outer dense fiber, and the annulus were also described. The similarities and differences between sperm flagella and Chlamydomonas flagella/somatic cell cilia were also discussed. Conclusion The molecular mechanism of formation of the sperm head and flagellum has been clarified using the mouse as a model. These studies will help to better understand the diversity of sperm morphology and the causes of male infertility.

show abstract

Section: Proteins Compose the Axonemal Structuresupporting

confidence: 73%

Molecular basis of the morphogenesis of sperm head and tail in mice

Yogo

2022

Reprod Medicine & Biology

View full text Add to dashboard Cite

show abstract

“…Motile cilia or flagella are evolutionarily conserved from unicellular protozoa to mammals 14 . Sperm flagella typically comprise a “9 + 2” axonemal arrangement and a number of multi-protein complexes, including outer dense fiber (ODF), fibrous sheath (FS), nexin-dynein regulatory complex (N-DRC), calmodulin-and spoke-associated complex(CSC) and dynein arms(DAs) 15 .…”

Section: Introductionmentioning

confidence: 99%

“…Sperm flagella typically comprise a “9 + 2” axonemal arrangement and a number of multi-protein complexes, including outer dense fiber (ODF), fibrous sheath (FS), nexin-dynein regulatory complex (N-DRC), calmodulin-and spoke-associated complex(CSC) and dynein arms(DAs) 15 . Among these protein complexes, the inner dynein arms (IDAs) composed of two heavy chains 1αHC (DNAH10, in mammals, similarly hereinafter) and 1β HC (DNAH2), three intermediate chains, IC140 (WDR63), IC138 (WDR78) and IC97 (LAS1) and several light chains in Chlamydomonas 14 , 16 . This subcomplex is absolutely required for flagella integrity and assembly, and is responsible for cilia (or flagella) beat frequency and bend formation 16 .…”

Section: Introductionmentioning

confidence: 99%

Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly

Lü

et al. 2021

Cell Discov

Self Cite

View full text Add to dashboard Cite

Inner dynein arm (IDA), composed of a series of protein complex, is necessary to cilia and flagella bend formation and beating. Previous studies indicated that defects of IDA protein complex result in multiple morphological abnormalities of the sperm flagellum (MMAF) and male infertility. However, the genetic causes and molecular mechanisms in the IDAs need further exploration. Here we identified two loss-of-function variants of WDR63 in both MMAF and non-obstructive azoospermia (NOA) affected cohorts. WDR63 encodes an IDA-associated protein that is dominantly expressed in testis. We next generated Wdr63-knockout (Wdr63-KO) mice through the CRISPR-Cas9 technology. Remarkably, Wdr63-KO induced decreased sperm number, abnormal flagellar morphology and male infertility. In addition, transmission electron microscopy assay showed severely disorganized “9 + 2” axoneme and absent inner dynein arms in the spermatozoa from Wdr63-KO male mice. Mechanistically, we found that WDR63 interacted with WDR78 mainly via WD40-repeat domain and is necessary for IDA assembly. Furthermore, WDR63-associated male infertility in human and mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. In conclusion, the present study demonstrates that bi-allelic variants of WDR63 cause male infertility via abnormal inner dynein arms assembly and flagella formation and can be used as a genetic diagnostic indicator for infertility males.

show abstract

“…Genomic DNA from whole peripheral blood samples was extracted using a QIAamp DNA Blood Midi Kit (Qiagen, Düsseldorf, Germany), according to the manufacturer’s protocol. Genomic DNA was prepared using the Agilent SureSelect Human All Exon V6 Kit and sequenced using the Illumina HiSeq 2000 or HiSeq X-TEN platform, as described previously 22 23. The original data were mapped to the human genome assembly (GRCh37/hg19) using Burrows-Wheeler Aligner software.…”

Section: Methodsmentioning

confidence: 99%

BiallelicCFAP61variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia

Meng

Tan

et al. 2022

J Med Genet

Self Cite

View full text Add to dashboard Cite

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 from 325 infertile patients with OAT and 392 fertile individuals. In silico and in vitro analyses were performed to evaluate the impacts of candidate disease-causing variants. A knockout mouse model was generated to confirm the candidate disease-causing gene, and intracytoplasmic sperm injection (ICSI) was used to evaluate the efficiency of clinical treatment.ResultsWe identified biallelic 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.ConclusionsOur findings indicate that CFAP61 is essential for spermatogenesis and that biallelic CFAP61 variants lead to male infertility in humans and mice with OAT.

show abstract

Bi-allelic mutations of DNAH10 cause primary male infertility with asthenoteratozoospermia in humans and mice

Cited by 57 publications

References 52 publications

Molecular basis of the morphogenesis of sperm head and tail in mice

Molecular basis of the morphogenesis of sperm head and tail in mice

Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly

BiallelicCFAP61variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia

Contact Info

Product

Resources

About