A homozygous CEP135 mutation is associated with multiple morphological abnormalities of the sperm flagella (MMAF)

Sha, Yanwei; Xu, Xiaohui; Mei, Libin; Li, Ping; Su, Zhiying; He, Xiaoqin; Li, Lin

doi:10.1016/j.gene.2017.08.033

Cited by 111 publications

(89 citation statements)

References 24 publications

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“…There were no statistically significant differences in ICSI outcome between the DNAH1 + group and the age-matched control group (Wambergue et al, 2016). In our report, we did not identify statistically significant differences in the rates of transferable embryos, implantation, clinical pregnancy and miscarriage between the CFAP44 + and DNAH1 + groups ( Previously, we reported about an MMAF patient with a CEP135 homozygous mutation from a consanguineous family (Sha, Xu, et al, 2017). The patient's spermatozoon was used to perform ICSI, but pregnancy failed after embryo transplantation (Sha, Xu, et al, 2017).…”

Section: Discussioncontrasting

confidence: 61%

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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Section: Discussioncontrasting

confidence: 61%

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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“…However, DNAH2 immunostaining was very weak and was barely detected in the sperm from P2 (Figure C). In order to determine if the loss of DNAH2 was a common feature of the MMAF phenotype, we also analyzed MMAF patients with CFAP43 , CFAP44 and CEP135 mutations that were previously reported . In these patients, DNAH2 expression was still comparable with that observed in the controls (Figure C).…”

Section: Resultsmentioning

confidence: 86%

“…The immunofluorescence staining methods of the spermatozoa were performed as previously described . The primary antibodies used are as follows: primary rabbit anti‐DNAH2 antibody (NBP2‐49506, Novus, Abingdon, UK), primary rabbit anti‐DNALI1 (17601‐1‐AP, Proteintech Group, Wuhan, China), primary rabbit anti‐AKAP4 (ab230954, Abcam, Cambridge, Massachusetts), primary rabbit anti‐RSPH1 (NBP1‐89840, Novus), primary mouse anti‐Tubulin antibody (66031‐1‐Ig, Proteintech Group, Wuhan, China), primary mouse anti‐DNAI2 antibody (H00064446‐MO1, Novus).…”

Section: Methodsmentioning

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 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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“…Since 2014, when MMAF was defined, studies have shown that mutations in genes associated with sperm flagellum development may lead to MMAF . Here, another candidate gene, CFAP65 , was identified in an infertile male with MMAF by WES.…”

Section: Discussionmentioning

confidence: 95%

“…The genetic basis of male infertility is still a work in progress, more than 4000 genes are expressed in germ cells during sperm production, and variations in these genes may hamper spermatogenesis . Recent studies of families with positive history related to male infertility have reported that mutations in cilia‐related genes are responsible for MMAF (eg, DNAH1 , CFAP43 , CFAP44 , CFAP69 , CFAP251 , QRICH2 , AK7 , CEP135 , FSIP2 , SPEF2 , TTC21A , ARMC2 , AKAP4 , CCDC39 ) . However, the known genetic defects can only explain ~60% of the individuals affected by MMAF …”

Section: Introductionmentioning

confidence: 99%

A novel homozygous CFAP65 mutation in humans causes male infertility with multiple morphological abnormalities of the sperm flagella

et al. 2019

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Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare autosomal recessive inherited disorder associated with male infertility. To date, 14 genetic causative genes have been identified in MMAF, which can only explain the genetic causes of ~60% of MMAF cases. Here, we report a man with primary infertility, who had a typical MMAF phenotype. Whole‐exome sequencing (WES) was performed on the patient and a homozygous mutation (c. 2675 G>A [p. Trp892*]) was identified in cilia and flagella‐associated protein 65 (CFAP65) gene, which is primarily expressed in the testis. Another loss‐of‐function mutation of CFAP65 has been detected in a MMAF patient, and the orthologue of CFAP65 also plays a vital role in sperm motility in chickens. Our experimental observations on human subjects suggested that CFAP65 is involved in sperm flagellum structure and assembly and that loss‐of‐function mutations could lead to male infertility in humans by causing the MMAF phenotype.

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A homozygous CEP135 mutation is associated with multiple morphological abnormalities of the sperm flagella (MMAF)

Cited by 111 publications

References 24 publications

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

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

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

A novel homozygous CFAP65 mutation in humans causes male infertility with multiple morphological abnormalities of the sperm flagella

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