DNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the Han Chinese population

Sha, Yanwei; Yang, Xiaoyu; Mei, Libin; Ji, Zhiyong; Wang, Xu; Ding, Lu; Li, Ping; Yang, Shenmin

doi:10.1016/j.fertnstert.2017.04.007

Cited by 81 publications

(77 citation statements)

References 24 publications

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“…Thus, the mutations in DNAH2 gene may be the main causes of the ablation of DNAH2 protein and the defects of flagella in patient's spermatozoa. Missense/nonsense, frameshift and essential splice‐site mutations in DNAH1 , which encodes another axonemal inner arm DHC protein, could also significantly decrease the protein expression and cause the MMAF phenotype . These studies in DNAH1 and DNAH2 reveal an essential role of DHC family proteins in the maintenance of the structural integrity of the flagella and suggest that other DHC‐encoding genes with unidentified functions might be involved in the sperm flagellar defects phenotype.…”

Section: Discussionmentioning

confidence: 89%

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DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella

Sha

Wang

et al. 2019

Clinical Genetics

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Multiple morphological abnormalities of flagella (MMAF) is one kind of severe teratozoospermia. Gene mutations reported in previous works only revealed the pathogenesis of approximately half of the MMAF cases, and more genetic defects in MMAF need to be explored. In the present study, we performed a genetic analysis on Han Chinese men with MMAF using whole‐exome sequencing. After filtering out the cases with known gene mutations, we identified five novel mutation sites in the DNAH2 gene in three cases from three families. These mutations were validated through Sanger sequencing and absent in all control individuals. In silico analysis revealed that these DNAH2 variations are deleterious. The spermatozoa with DNAH2 mutations showed severely disarranged axonemal structures with mitochondrial sheath defection. The DNAH2 protein level was significantly decreased and inner dynein arms were absent in the spermatozoa of patients. ICSI treatment was performed for two MMAF patients with DNAH2 mutations and the associated couples successfully achieved pregnancy, indicating good nuclear quality of the sperm from the DNAH2 mutant patients. Together, these data suggest that the DNAH2 mutation can cause severe sperm flagella defects that damage sperm motility. These results provide a novel genetic pathogeny for the human MMAF phenotype.

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Section: Discussionmentioning

confidence: 89%

“…Until now, only a few gene autosomal variants have been reported to cause MMAF phenotype in infertile man, such as AKAP4 , DNAH1 , CFP43 , CFP44 and FISP2 . Among these genes, DNAH1 is believed to be the main genetic contributor .…”

Section: Discussionmentioning

confidence: 99%

DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella

Sha

Wang

et al. 2019

Clinical Genetics

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“…Multiple studies have indicated that biallelic mutations in DNAH1, CFAP43 and CFAP44, which occur with a frequency that is independent of genetic origin, cause the majority of MMAF cases (Amiri-Yekta et al, 2016;Ben Khelifa et al, 2014;Sha et al, 2018;Sha, Yang, et al, 2017;Tang et al, 2017;Wang et al, 2017). Multiple studies have indicated that biallelic mutations in DNAH1, CFAP43 and CFAP44, which occur with a frequency that is independent of genetic origin, cause the majority of MMAF cases (Amiri-Yekta et al, 2016;Ben Khelifa et al, 2014;Sha et al, 2018;Sha, Yang, et al, 2017;Tang et al, 2017;Wang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Molecular genetic testing by whole-exome sequencing identified 12 MMAF patients with homozygous or compound heterozygous DNAH1 mutations (DNAH1 + group; Sha, Yang, et al, 2017) and six patients with biallelic CFAP44 (CFAP44 + group) or CFAP43 mutations (Sha et al, 2018). MMAF patients and non-MMAF subjects (age-matched control group) were recruited from the Xiamen Maternity and Child Care Hospital (Xiamen, China) and the Affiliated Yantai Yuhuangding Hospital of Qingdao University (Qingdao, China).…”

Section: Patients and Controlsmentioning

confidence: 99%

“…Multiple morphological abnormalities of the sperm flagella have been recently identified as a genetic disease based on its association with biallelic mutations of DNAH1, CFAP43 and CFAP44 (Amiri-Yekta et al, 2016;Ben Khelifa et al, 2014;Sha et al, 2018;Sha, Yang, et al, 2017;Tang et al, 2017;Wang et al, 2017), which occur in approximately 50%-70% of MMAF patients. In a minority of MMAF patients, other mutations, such as AKAP4, CCDC39, CFAP65 and CEP135 mutations, could be involved (Baccetti et al, 2005;Merveille et al, 2011;Sha, Xu, et al, 2017;Tang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Patients with multiple morphological abnormalities of the sperm flagella harbouring CFAP44 or CFAP43 mutations have a good pregnancy outcome following intracytoplasmic sperm injection

Sha

Wang

et al. 2018

Andrologia

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Multiple morphological abnormalities of the sperm flagella (MMAF) are a rare type of male infertility. Mutations in DNAH1, CFAP43 and CFAP44 are the main aetiology of the disorder. Previously, good intracytoplasmic sperm injection (ICSI) outcomes were reported for MMAF patients with DNAH1 mutations. However, the ICSI prognosis for MMAF patients with CFAP43 or CFAP44 mutations was not known. We designed a retrospective cohort study. Molecular genetic testing identified six MMAF patients with biallelic CFAP44 (CFAP44+ group) or CFAP43 mutations and 12 patients with homozygous or compound heterozygous DNAH1 mutations (DNAH1+ group). A control group consisted of age‐matched, non‐MMAF men. For MMAF patients carrying CFAP44 mutations, the recorded rates of fertilisation, transferable embryos, pregnancy and delivery after ICSI were 76.47%, 88.46%, 50.0% and 50.0% respectively. The fertilisation rate was significantly higher in the CFAP44+ group than in the DNAH1+ group (76.47% vs. 54.5%, p = 0.0196). There were no statistically significant differences in the rates of transferable embryos, implantation, clinical pregnancy and miscarriage between the CFAP44+ group and either the DNAH1+ group or the age‐matched control group. Our results support a good ICSI prognosis for MMAF patients carrying CFAP44 or CFAP43 mutations.

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Functional and structural significance of the inner‐arm‐dynein subspecies d in ciliary motility

Yamamoto,

Kon

2024

Cytoskeleton

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Motile cilia play various important physiological roles in eukaryotic organisms including cell motility and fertility. Inside motile cilia, large motor‐protein complexes called “ciliary dyneins” coordinate their activities and drive ciliary motility. The ciliary dyneins include the outer‐arm dyneins, the double‐headed inner‐arm dynein (IDA f/I1), and several single‐headed inner‐arm dyneins (IDAs a, b, c, d, e, and g). Among these single‐headed IDAs, one of the ciliary dyneins, IDA d, is of particular interest because of its unique properties and subunit composition. In addition, defects in this subspecies have recently been associated with several types of ciliopathies in humans, such as primary ciliary dyskinesia and multiple morphologic abnormalities of the flagellum. In this mini‐review, we discuss the composition, structure, and motor properties of IDA d, which have been studied in the model organism Chlamydomonas reinhardtii, and further discuss the relationship between IDA d and human ciliopathies. In addition, we provide future perspectives and discuss remaining questions regarding this intriguing dynein subspecies.

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DNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the Han Chinese population

Abstract: These DNAH1 gene mutations may be associated with DFS and infertility in the Han population.

Cited by 81 publications

References 24 publications

DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella

DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella

Patients with multiple morphological abnormalities of the sperm flagella harbouring CFAP44 or CFAP43 mutations have a good pregnancy outcome following intracytoplasmic sperm injection

Functional and structural significance of the inner‐arm‐dynein subspecies d in ciliary motility

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