Patients with multiple morphological abnormalities of the sperm flagella due to<i>DNAH1</i>mutations have a good prognosis following intracytoplasmic sperm injection

Wambergue, Clémentine; Zouari, Raoudha; Mustapha, Sélima Fourati Ben; Martinez, Guillaume; Devillard, Françoise; Hennebicq, Sylviane; Satre, Véronique; Brouillet, Sophie; Halouani, Lazhar; Marrakchi, Ouafi; Makni, Mounir; Latrous, Habib; Kharouf, Mahmoud; Amblard, Florence; Arnoult, Christophe; Ray, Pierre F.; Coutton, Charles

doi:10.1093/humrep/dew083

Cited by 103 publications

(68 citation statements)

References 23 publications

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“…This abnormal sperm flagella phenotype was previously reported as dysplasia of the fibrous sheath or short/stump tail syndromes and occurs in more than 1 per 10 000 to 20 000 births . Patients with this phenotype could not achieve spontaneous pregnancy or fertilization in vitro, but a high success rate of intracytoplasmic sperm injection could be observed in some individuals with MMAF …”

Section: Introductionmentioning

confidence: 79%

“…[4][5][6] Patients with this phenotype could not achieve spontaneous pregnancy or fertilization in vitro, but a high success rate of intracytoplasmic sperm injection could be observed in some individuals with MMAF. 7 Previous studies demonstrated that MMAF was caused by genetic defects in several testis-specific genes. 1 Biallelic mutations in DNAH1, which encode an axonemal inner arm dynein, are responsible for 28%-44% of all MMAF patients.…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

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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“…Numerous studies have reported an increased rate of aneuploidy and a poor sperm nuclear quality related to sperm flagellar abnormalities, which could impede ICSI outcome (37). However, MMAF patients with DNAH1 mutations combine low aneuploidy rates and a good nuclear sperm quality leading to good ICSI results (106). Of course we cannot consider that it is the presence of DNAH1 mutations which are responsible for the good nuclear quality of the sperm but merely that many others patients with different defects do not have such good parameters and do not perform as well following ICSI.…”

Section: Multiple Morphological Abnormalities Of the Sperm Flagella (mentioning

confidence: 99%

Genetic abnormalities leading to qualitative defects of sperm morphology or function

et al. 2016

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Infertility, defined by the inability of conceiving a child after 1 year is estimated to concern approximately 50 million couples worldwide. As the male gamete is readily accessible and can be studied by a simple spermogram it is easier to subcategorize male than female infertility. Subjects with a specific sperm phenotype are more likely to have a common origin thus facilitating the search for causal factors. Male infertility is believed to be often multifactorial and caused by both genetic and extrinsic factors, but severe cases of male infertility are likely to have a predominant genetic etiology. Patients presenting with a monomorphic teratozoospermia such as globozoospermia or macrospermia with more than 85% of the spermatozoa presenting this specific abnormality have been analyzed permitting to identify several key genes for spermatogenesis such as AURKC and DPY19L2. The study of patients with other specific sperm anomalies such as severe alteration of sperm motility, in particular multiple morphological anomalies of the sperm flagella (MMAF) or sperm unability to fertilize the oocyte (oocyte activation failure syndrome) has also enable the identification of new infertility genes. Here we review the recent works describing the identification and characterization of gene defects having a direct qualitative effect on sperm morphology or function.

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“…No success of spontaneous pregnancy or conventional in vitro fertilization has been previously reported for MMAF, but individuals with MMAF have had a good prognosis after intracytoplasmic sperm injection. 9 Previous studies on genetic mutants in model organisms have revealed genetic contributions to flagellar motility defects. 2,[10][11][12][13][14] So far, mutations in only three genes, AKAP4 (MIM: 300185), CCDC39 (MIM: 613798), and DNAH1 (MIM: 603332), have been formally identified to cause MMAF in humans.…”

Section: Introductionmentioning

confidence: 99%

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Tang¹,

Wang

Li³

et al. 2017

The American Journal of Human Genetics

254

212

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Sperm motility is vital to human reproduction. Malformations of sperm flagella can cause male infertility. Men with multiple morphological abnormalities of the flagella (MMAF) have abnormal spermatozoa with absent, short, coiled, bent, and/or irregular-caliber flagella, which impair sperm motility. The known human MMAF-associated genes, such as DNAH1, only account for fewer than 45% of affected individuals. Pathogenic mechanisms in the genetically unexplained MMAF remain to be elucidated. Here, we conducted genetic analyses by using whole-exome sequencing and genome-wide comparative genomic hybridization microarrays in a multi-center cohort of 30 Han Chinese men affected by MMAF. Among them, 12 subjects could not be genetically explained by any known MMAFassociated genes. Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject. All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations. CFAP43 and CFAP44, encoding two cilia-and flagella-associated proteins (CFAPs), are specifically or preferentially expressed in the testis. Using CRISPR/Cas9 technology, we generated two knockout models each deficient in mouse ortholog Cfap43 or Cfap44. Notably, both Cfap43-and Cfap44-deficient male mice presented with MMAF phenotypes, whereas the corresponding female mice were fertile. Our experimental observations on human subjects and animal models strongly suggest that biallelic mutations in either CFAP43 or CFAP44 can cause sperm flagellar abnormalities and impair sperm motility. Further investigations on other CFAP-encoding genes in more genetically unexplained MMAF-affected individuals could uncover novel mechanisms underlying sperm flagellar formation.

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Patients with multiple morphological abnormalities of the sperm flagella due toDNAH1mutations have a good prognosis following intracytoplasmic sperm injection

Cited by 103 publications

References 23 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

Genetic abnormalities leading to qualitative defects of sperm morphology or function

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

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