Whole-exome sequencing identifies mutations in FSIP2 as a recurrent cause of multiple morphological abnormalities of the sperm flagella

Martinez, Guillaume; Kherraf, Zine‐Eddine; Zouari, Raoudha; Mustapha, Sélima Fourati Ben; Saut, Antoine; Pernet‐Gallay, Karin; Bertrand, Anne; Bidart, Marie; Hograindleur, Jean Pascal; Amiri-Yekta, Amir; Kharouf, Mahmoud; Karaouzène, Thomas; Thierry‐Mieg, Nicolas; Dacheux, Denis; Satre, Véronique; Bonhivers, Mélanie; Touré, Aminata; Arnoult, Christophe; Ray, Pierre F.; Coutton, Charles

doi:10.1093/humrep/dey264

Cited by 101 publications

(101 citation statements)

References 55 publications

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“…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 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: 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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“…The genetic characterization of this phenotype began in 2014 with the identification of DNAH1 (dynein axonemal heavy chain 1) as a major gene implicated in MMAF . After the development and the introduction of high throughput sequencing (HTS) techniques such as whole exome sequencing (WES), deleterious mutations were formally identified in eight additional MMAF genes ( AK7 , ARMC2 , CFAP43 , CFAP44 , CFAP69 , FSIP2 , TTC21A , and WDR66 ) showing the high genetic heterogeneity of this phenotype. Despite these important advances in gene identification, about half of the MMAF cases remain idiopathic without a genetic diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Whole exome sequencing of men with multiple morphological abnormalities of the sperm flagella reveals novel homozygous QRICH2 mutations

et al. 2019

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Multiple morphological anomalies of the sperm flagella (MMAF syndrome) is a severe male infertility phenotype which has so far been formally linked to the presence of biallelic mutations in nine genes mainly coding for axonemal proteins overexpressed in the sperm flagellum. Homozygous mutations in QRICH2, a gene coding for a protein known to be required for stabilizing proteins involved in sperm flagellum biogenesis, have recently been identified in MMAF patients from two Chinese consanguineous families. Here, in order to better assess the contribution of QRICH2 in the etiology of the MMAF phenotype, we analyzed all QRICH2 variants from whole exome sequencing data of a cohort of 167 MMAF‐affected subjects originating from North Africa, Iran, and Europe. We identified a total of 14 potentially deleterious variants in 18 unrelated individuals. Two unrelated subjects, representing 1% of the cohort, carried a homozygous loss‐of‐function variant: c.3501C>G [p.Tyr1167Ter] and c.4614C>G [p.Tyr1538Ter], thus confirming the implication of QRICH2 in the MMAF phenotype and human male infertility. Sixteen MMAF patients (9.6%) carried a heterozygous QRICH2 potentially deleterious variant. This rate was comparable to what was observed in a control group (15.5%) suggesting that the presence of QRICH2 heterozygous variants is not associated with MMAF syndrome.

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“…Many researchers have shown that the MMAF phenotype is associated with genetic mutations. Previous studies revealed that mutations in DNAH1 (MIM: 603332), DNAH2 (MIM: 603333), AKAP4 (MIM: 300185), CCDC39 (MIM: 613798), AK7 (MIM: 615364), CFAP251 (MIM: 618146), CEP135 (MIM: 611423), FSIP2 (MIM: 615796), ARMC2 (MIM: 611226), QRICH2 (MIM: 618304), SPEF2 (MIM: 610172), CFAP69 (MIM: 617949), CFAP43 (MIM: 617558) and CFAP44 (MIM:617559) could cause the human MMAF phenotype . However, more research is needed to reveal the etiology of the remaining 30%–40% of MMAF cases.…”

Section: Introductionmentioning

confidence: 99%

Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype

et al. 2019

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Male patients with multiple morphological abnormalities of the sperm flagella (MMAF) are infertile and exhibit absent, short, coiled, bent and/or irregular sperm flagella. Mutations in the SPEF2 gene reduce sperm motility and cause sperm tail defects in animal models and humans. In the present study, we performed a genetic analysis on an MMAF patient and identified novel biallelic mutations in the SPEF2 gene. The biallelic mutations were confirmed by Sanger sequencing and in silico analysis revealed that, these variations were deleterious. The expression of truncated SPEF2 protein was reduced significantly in the patient's spermatozoa. The spermatozoa harbored biallelic mutations and showed severe ultrastructural defects in the axoneme and mitochondrial sheath. Our data suggest that biallelic mutations in SPEF2 can cause severe sperm flagellum defects, thus providing a novel candidate genetic pathogen for the human MMAF phenotype.

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Whole-exome sequencing identifies mutations in FSIP2 as a recurrent cause of multiple morphological abnormalities of the sperm flagella

Cited by 101 publications

References 55 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

Whole exome sequencing of men with multiple morphological abnormalities of the sperm flagella reveals novel homozygous QRICH2 mutations

Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype

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