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Cited by 245Sperm and Testicular FunctionCystic Fibrosis Research AdvancesGenetic and Kidney Cyst Diseases

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Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human

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Coutton, Charles, Vargas, Alexandra S., Amiri-Yekta, Amir, Kherraf, Zine-Eddine, Ben Mustapha, Selima Fourati, Le Tanno, Pauline, Wambergue-Legrand, Clémentine, Karaouzène, Thomas, Martinez, Guillaume, Crouzy, Serge, Daneshipour, Abbas, Hosseini, Seyedeh Hanieh, Mitchell, Valérie, Halouani, Lazhar, Marrakchi, Ouafi, Makni, Mounir, Latrous, Habib, Kharouf, Mahmoud, Deleuze, Jean-François, Boland, Anne, Hennebicq, Sylviane, Satre, Véronique, Jouk, Pierre-Simon, Thierry-Mieg, Nicolas, Conne, Beatrice, Dacheux, Denis, Landrein, Nicolas, Schmitt, Alain, Stouvenel, Laurence, Lorès, Patrick, El Khouri, Elma, Bottari, Serge P., Fauré, Julien, Wolf, Jean-Philippe, Pernet-Gallay, Karin, Escoffier, Jessica, Gourabi, Hamid, Robinson, Derrick R., Nef, Serge, Dulioust, Emmanuel, Zouari, Raoudha, Bonhivers, Mélanie, Touré, Aminata, Arnoult, Christophe, Ray, Pierre F.·2018·Nature Communications
DOI 10.1038/s41467-017-02792-7PMC PMC5814398
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Abstract

Spermatogenesis defects concern millions of men worldwide, yet the vast majority remains undiagnosed. Here we report men with primary infertility due to multiple morphological abnormalities of the sperm flagella with severe disorganization of the sperm axoneme, a microtubule-based structure highly conserved throughout evolution. Whole-exome sequencing was performed on 78 patients allowing the identification of 22 men with bi-allelic mutations in DNAH1 ( n = 6), CFAP43 ( n = 10), and CFAP44 ( n = 6). CRISPR/Cas9 created homozygous CFAP43 / 44 male mice that were infertile and presented severe flagellar defects confirming the human genetic results. Immunoelectron and stimulated-emission-depletion microscopy performed on CFAP43 and CFAP44 orthologs in Trypanosoma brucei evidenced that both proteins are located between the doublet microtubules 5 and 6 and the paraflagellar rod. Overall, we demonstrate that CFAP43 and CFAP44 have a similar structure with a unique axonemal localization and are necessary to produce functional flagella in species ranging from Trypanosoma to human.

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Fig. 1 Morphology of spermatozoa from the patients P43-8 and P44-3 and position of CFAP43 and CFAP44 mutations in the intron–exon structure and in the protein. a All spermatozoa have a much shorter flagellum than those of controls. Additional features of MMAF spermatozoa are absent (*), thick (&), and rolled flagella (@). b Mutations identified in the CFAP43 gene. c Mutations identified in the CFAP44 gene. Blue squares stand for WD repeat domains and green squares for coiled-coiled domains as described by Uniprot server. Mutations are annotated in accordance to the HGVS’s recommendations
Fig. 1 Morphology of spermatozoa from the patients P43-8 and P44-3 and position of CFAP43 and CFAP44 mutations in the intron–exon structure and in the protein. a All spermatozoa have a much shorter flagellum than those of controls. Additional features of MMAF spermatozoa are absent (*), thick (&), and rolled flagella (@). b Mutations identified in the CFAP43 gene. c Mutations identified in the CFAP44 gene. Blue squares stand for WD repeat domains and green squares for coiled-coiled domains as described by Uniprot server. Mutations are annotated in accordance to the HGVS’s recommendationsCC BY · PubMed Central
Fig. 2 Transmission electron microscopy analysis of sperm cells from CFAP43 and CFAP44 patients shows a severe axonemal disorganization. (Left panel) Longitudinal sections (scale bar = 500 nm) and cross-sections (scale bars, 100 nm) of sperm flagellum from control. (Central panel) Longitudinal sections (scale bars, 500 nm) and cross-sections (scale bars, 100 nm) of sperm flagellum from CFAP43-mutated patient (P43-8). We can notice a short short tail corresponding to a cytoplasmic mass containing the different components of the flagellum, all unorganized. In CFAP43 upper cross-section, the CPC is not aligned with DMTs 3 and 8 (red line) and is rotated by 90°. We can observe the absence of central pair of microtubules in other cross-sections. (Right panel) Ultrastructure of CFAP44-mutated sperm (P44-3) longitudinal sections (scale bars = 500 nm) show similar ultrastructure of short tail (cytoplasmic mass). In CFAP44 upper cross-section, the central pair is disassembled and displaced (red arrow). We can observe the absence of central pair of microtubules in other cross-sections. Scales bars for cross-sections = 100 nm
Fig. 2 Transmission electron microscopy analysis of sperm cells from CFAP43 and CFAP44 patients shows a severe axonemal disorganization. (Left panel) Longitudinal sections (scale bar = 500 nm) and cross-sections (scale bars, 100 nm) of sperm flagellum from control. (Central panel) Longitudinal sections (scale bars, 500 nm) and cross-sections (scale bars, 100 nm) of sperm flagellum from CFAP43-mutated patient (P43-8). We can notice a short short tail corresponding to a cytoplasmic mass containing the different components of the flagellum, all unorganized. In CFAP43 upper cross-section, the CPC is not aligned with DMTs 3 and 8 (red line) and is rotated by 90°. We can observe the absence of central pair of microtubules in other cross-sections. (Right panel) Ultrastructure of CFAP44-mutated sperm (P44-3) longitudinal sections (scale bars = 500 nm) show similar ultrastructure of short tail (cytoplasmic mass). In CFAP44 upper cross-section, the central pair is disassembled and displaced (red arrow). We can observe the absence of central pair of microtubules in other cross-sections. Scales bars for cross-sections = 100 nmCC BY · PubMed Central
Fig. 3 Immunofluorescence staining in CFAP43 and CFAP44 patients reveals an abnormal axonemal organization. a–c sperm cells from a fertile control stained with anti SPAG6 (green), a protein located in the CPC, and anti-acetylated tubulin (red) antibodies. DNA was counterstained with Hoechst 33342. c Corresponds to a and b overlay and shows that in control sperm, SPAG6 and tubulin staining superimpose. Scale bars = 5 µm. d–f SPAG6 staining is absent in sperm from the patient P43-5 homozygous for the c.2658C>T variant in CFAP43. d–i Similar IF experiments performed with sperm cells from the patient P44-2 homozygous for the c.3175C>T variant in CFAP44. Scale bar = 5 µm. Contrary to the control, the SPAG6 immunostaining (green) is abnormal with a diffuse pattern concentrated in the midpiece of the spermatozoa and is not detectable in the principle piece. j–l Sperm cells from a fertile control stained with anti RSPH1 (green), a protein of the radial spoke’s head, and anti-acetylated tubulin (red) antibodies. DNA was counterstained with Hoechst 33342. l corresponds to j and k overlay and shows that RSPH1 and tubulin staining superimpose in control sperm. Scale bar = 5 µm. m–o In sperm from the patient P43-5, RSPH1 staining (green) is significantly different from control (m) with a marked diffuse staining. p–r In sperm from the patient P44-2 the intensity of the RSPH1 staining is strongly reduced
Fig. 3 Immunofluorescence staining in CFAP43 and CFAP44 patients reveals an abnormal axonemal organization. a–c sperm cells from a fertile control stained with anti SPAG6 (green), a protein located in the CPC, and anti-acetylated tubulin (red) antibodies. DNA was counterstained with Hoechst 33342. c Corresponds to a and b overlay and shows that in control sperm, SPAG6 and tubulin staining superimpose. Scale bars = 5 µm. d–f SPAG6 staining is absent in sperm from the patient P43-5 homozygous for the c.2658C>T variant in CFAP43. d–i Similar IF experiments performed with sperm cells from the patient P44-2 homozygous for the c.3175C>T variant in CFAP44. Scale bar = 5 µm. Contrary to the control, the SPAG6 immunostaining (green) is abnormal with a diffuse pattern concentrated in the midpiece of the spermatozoa and is not detectable in the principle piece. j–l Sperm cells from a fertile control stained with anti RSPH1 (green), a protein of the radial spoke’s head, and anti-acetylated tubulin (red) antibodies. DNA was counterstained with Hoechst 33342. l corresponds to j and k overlay and shows that RSPH1 and tubulin staining superimpose in control sperm. Scale bar = 5 µm. m–o In sperm from the patient P43-5, RSPH1 staining (green) is significantly different from control (m) with a marked diffuse staining. p–r In sperm from the patient P44-2 the intensity of the RSPH1 staining is strongly reducedCC BY · PubMed Central
Fig. 4 Reproductive phenotype of homozygous and heterozygous Cfap43 and Cfap44 male mice. a Fertility of Cfap43+/−, Cfap44+/− Cfap43−/−, and Cfap44−/− males. Heterozygous and homozygous mutant males were mated with WT females and the numbers of pups per litter were measured. KO males were completely sterile. b, c Spermatocytograms showing the number of abnormal sperm in heterozygous and homozygous mutant males. d–f Images of typical sperm stained with Harris–Shorr from Cfap43−/− and Cfap44−/− males. Scale bars = 10 µm. g Total and progressive motilities of sperm from Cfap43−/− and Cfap44−/− males. h–m The mitochondria sheath is fragmented in Cfap44−/− males. Staining of WT sperm with an anti-MCPl1 (h, green), a mitochondrial transporter, and anti-acetylated tubulin (i, red) antibodies. j Overlay of MCPl1 and tubulin staining. Sperms were counterstained with Hoechst (blue). k–m Similar experiments on sperm from Cfap44−/− males. Scale bars = 10 µm. a–c, g Data represent mean ± SD; statistical differences were assessed with t test, P value as indicated
Fig. 4 Reproductive phenotype of homozygous and heterozygous Cfap43 and Cfap44 male mice. a Fertility of Cfap43+/−, Cfap44+/− Cfap43−/−, and Cfap44−/− males. Heterozygous and homozygous mutant males were mated with WT females and the numbers of pups per litter were measured. KO males were completely sterile. b, c Spermatocytograms showing the number of abnormal sperm in heterozygous and homozygous mutant males. d–f Images of typical sperm stained with Harris–Shorr from Cfap43−/− and Cfap44−/− males. Scale bars = 10 µm. g Total and progressive motilities of sperm from Cfap43−/− and Cfap44−/− males. h–m The mitochondria sheath is fragmented in Cfap44−/− males. Staining of WT sperm with an anti-MCPl1 (h, green), a mitochondrial transporter, and anti-acetylated tubulin (i, red) antibodies. j Overlay of MCPl1 and tubulin staining. Sperms were counterstained with Hoechst (blue). k–m Similar experiments on sperm from Cfap44−/− males. Scale bars = 10 µm. a–c, g Data represent mean ± SD; statistical differences were assessed with t test, P value as indicatedCC BY · PubMed Central
Fig. 5 The sperm axoneme from Cfap43−/− males is fully disorganized. a Central pair is absent in sperm from Cfap43−/− males. Staining of WT sperm with an anti-Spef2, a marker of the projection 1b of singlet C1 (a, green) and anti-acetylated tubulin (b, red) antibodies. c Overlay of Spef2 and tubulin staining. Sperms were counterstained with Hoechst (blue). d–f Similar experiments on sperm from Cfap43−/− males. Scale bars = 5 µm. g–l Head of radial spoke are absent in sperm from Cfap43−/− males. Staining of WT sperm with an anti-Rsph4a, another protein of the RS head (g, green) and anti-tubulin (h, red) antibodies. i Overlay of Rsph4a and tubulin staining. Sperm were counterstained with Hoechst (blue). j–l Similar experiments on sperm from Cfap43−/− males. Scale bars = 5 µm. m, n Transversal section of a sperm from WT (m) and Cfap43−/− (n) males observed by EM in the midpiece region. Note the specific arrangement of the ODFs around the axoneme in WT sperm and the complete disorganization of the DMTs and the absence of the central pair in Cfap43−/− sperm. Scale bars = 240 nm. Number of cross-section for WT and Cfap43−/− were 21 and 30, respectively. All cross-section were defective for Cfap43−/−. DMTs, doublet of microtubules; ODF, outer dense fiber; Mt, mitochondria
Fig. 5 The sperm axoneme from Cfap43−/− males is fully disorganized. a Central pair is absent in sperm from Cfap43−/− males. Staining of WT sperm with an anti-Spef2, a marker of the projection 1b of singlet C1 (a, green) and anti-acetylated tubulin (b, red) antibodies. c Overlay of Spef2 and tubulin staining. Sperms were counterstained with Hoechst (blue). d–f Similar experiments on sperm from Cfap43−/− males. Scale bars = 5 µm. g–l Head of radial spoke are absent in sperm from Cfap43−/− males. Staining of WT sperm with an anti-Rsph4a, another protein of the RS head (g, green) and anti-tubulin (h, red) antibodies. i Overlay of Rsph4a and tubulin staining. Sperm were counterstained with Hoechst (blue). j–l Similar experiments on sperm from Cfap43−/− males. Scale bars = 5 µm. m, n Transversal section of a sperm from WT (m) and Cfap43−/− (n) males observed by EM in the midpiece region. Note the specific arrangement of the ODFs around the axoneme in WT sperm and the complete disorganization of the DMTs and the absence of the central pair in Cfap43−/− sperm. Scale bars = 240 nm. Number of cross-section for WT and Cfap43−/− were 21 and 30, respectively. All cross-section were defective for Cfap43−/−. DMTs, doublet of microtubules; ODF, outer dense fiber; Mt, mitochondriaCC BY · PubMed Central
Fig. 6 Electron microscopy cross-sections of sperm from Cfap44−/− males reveal multiple structural axonemal defects. a Cross-section of the midpiece of a WT sperm, showing the arrangement of the ODFs around the axoneme. b Presence of extra ODFs in midpieces sections of sperm from Cfap44−/− males. The orientation of ODFs is also defective, leading to an increase of the midpiece diameter. a, b Same scale bars = 250 nm. c Graph showing the increased number of ODF in the mutant. Data represent mean ± SD; the statistical difference was assessed with t test, P value as indicated. Twenty-one cross-sections in the midpiece region were analyzed for WT and 21 for Cfap44−/−. d–f Various structural defects of the axoneme in sperm from Cfap44−/− males. d Four DMTs (4–7) were missing. The central pair is shifted at the periphery (red arrowhead). e DMTs 5–7 were missing. Note the presence of a third longitudinal column (LC). f Irregular distribution of the DMTs associated with a rotation of the central pair (straight red line). Scale bars = 196 nm. g In WT sperm, the fibrous sheath is linked to the 3-central-8 complex by stalks emerging from the longitudinal columns (white arrowheads). h, i The presence of extra ODFs facing DMTs 3 and 8 (red arrowheads) prevents a normal anchoring of the fibrous sheath’s stalks on DMTs 3 and 8. Scale bars = 270 nm. j–o LCs are not aligned with 3–8 CPC axis. In contrast to WT, where the 3-central-8 complex is aligned with LC to form almost a straight line (j, red line), LC are misaligned in sperm from Cfap44−/− males, leading to notable asymmetry of the structure (k, m, red lines). l, n The presence of a third LC increases asymmetry. Scale bars = 184 nm. o Bar graph showing the % of defects observed in the principal piece as described in g–n. One hundred cross-sections in the principal piece region were analyzed for WT and 50 for Cfap44−/−
Fig. 6 Electron microscopy cross-sections of sperm from Cfap44−/− males reveal multiple structural axonemal defects. a Cross-section of the midpiece of a WT sperm, showing the arrangement of the ODFs around the axoneme. b Presence of extra ODFs in midpieces sections of sperm from Cfap44−/− males. The orientation of ODFs is also defective, leading to an increase of the midpiece diameter. a, b Same scale bars = 250 nm. c Graph showing the increased number of ODF in the mutant. Data represent mean ± SD; the statistical difference was assessed with t test, P value as indicated. Twenty-one cross-sections in the midpiece region were analyzed for WT and 21 for Cfap44−/−. d–f Various structural defects of the axoneme in sperm from Cfap44−/− males. d Four DMTs (4–7) were missing. The central pair is shifted at the periphery (red arrowhead). e DMTs 5–7 were missing. Note the presence of a third longitudinal column (LC). f Irregular distribution of the DMTs associated with a rotation of the central pair (straight red line). Scale bars = 196 nm. g In WT sperm, the fibrous sheath is linked to the 3-central-8 complex by stalks emerging from the longitudinal columns (white arrowheads). h, i The presence of extra ODFs facing DMTs 3 and 8 (red arrowheads) prevents a normal anchoring of the fibrous sheath’s stalks on DMTs 3 and 8. Scale bars = 270 nm. j–o LCs are not aligned with 3–8 CPC axis. In contrast to WT, where the 3-central-8 complex is aligned with LC to form almost a straight line (j, red line), LC are misaligned in sperm from Cfap44−/− males, leading to notable asymmetry of the structure (k, m, red lines). l, n The presence of a third LC increases asymmetry. Scale bars = 184 nm. o Bar graph showing the % of defects observed in the principal piece as described in g–n. One hundred cross-sections in the principal piece region were analyzed for WT and 50 for Cfap44−/−CC BY · PubMed Central
Fig. 7 Orthologs of T. brucei TbCFAP44 and TbCFAP43 are flagellar proteins apposed to DMTs 5–6. a–f STED confocal microscopy, deconvolution, and 3D reconstruction views of the co-labeling, on permeabilized whole cells, of tubulin (green), PFR2 (gray), and 10TY1TbCFAP44 (a–c) and 10TY1TbCFAP43 (d–f) showing that TbCFAP44 and TbCFAP43 are facing the PFR and are closely associated with the tubulin, which likely corresponds to DMTs 5–6. Scale bars=0.5 μm. g–j Electron immunogold labeling of cytoskeleton-extracted cells expressing TbCFAP44myc (g) and TbCFAP43myc (h). Controls with no primary antibody (i) and anti-PFR2 (j). Gold beads size was either 6 nm (g, h) or 10 nm (i, j). Scale bars=200 nm in g, h; 100 nm in i, j. Insets are enlargement of images of flagella taken from the main panels and scale bars=10 nm
Fig. 7 Orthologs of T. brucei TbCFAP44 and TbCFAP43 are flagellar proteins apposed to DMTs 5–6. a–f STED confocal microscopy, deconvolution, and 3D reconstruction views of the co-labeling, on permeabilized whole cells, of tubulin (green), PFR2 (gray), and 10TY1TbCFAP44 (a–c) and 10TY1TbCFAP43 (d–f) showing that TbCFAP44 and TbCFAP43 are facing the PFR and are closely associated with the tubulin, which likely corresponds to DMTs 5–6. Scale bars=0.5 μm. g–j Electron immunogold labeling of cytoskeleton-extracted cells expressing TbCFAP44myc (g) and TbCFAP43myc (h). Controls with no primary antibody (i) and anti-PFR2 (j). Gold beads size was either 6 nm (g, h) or 10 nm (i, j). Scale bars=200 nm in g, h; 100 nm in i, j. Insets are enlargement of images of flagella taken from the main panels and scale bars=10 nmCC BY · PubMed Central
Fig. 8 T. brucei CFAP44 and CFAP43 are necessary for cell survival and proper axonemal organization. a–d Immunofluorescence on detergent-extracted cells of parental T. brucei stained with anti-PFR (red) and anti-myc (green) antibodies. e–h Immunofluorescence on detergent-extracted cells expressing TbCFAP44myc and RNAi induced (24 h) for TbCFAP44 (TbCFAP44mycRNAi). Cells showed no or weak myc labeling (green) on the new flagellum (NF), while the old flagellum (OF) remained labeled. PFR is labeled in red. Note: cells with a maximum of two flagella were chosen for clear imaging. i–l Similar RNAi experiments as performed in e–h for TbCFAP43 RNAi in cells expressing TbCFAP43myc (TbCFAP43mycRNAi). Cells showed no or weak myc labeling (green) on the new flagellum (NF), while the old flagellum (OF) remained labeled. PFR is labeled in red. Nuclei and kinetoplasts (mitochondrial genome) are labeled with DAPI (blue). Scale bars=5 μm. Insets are enlargement of images of flagella taken from the main panels and display areas indicated by white arrows (scale bar=1 µm). m Growth curves for parental cells, and TbCFAP44RNAi and TbCFAP43RNAi cells, non-induced or induced with tetracycline. The graph represents the cumulative number of cells per ml. Error bars represent the standard error from three independent experiments. n Flagellum length measurement of the new flagellum in cells bearing two flagella from parental cells, and from cells expressing TbCFAP44myc and TbCFAP44myc and induced (24 h) for TbCFAP44 RNAi and TbCFAP43 RNAi, respectively. Flagellum length was measured in cells showing a clear decrease in myc labeling in the new flagellum. o–t Electron micrographs of stained thin sections of parental cells (o, r) bearing one flagellar pocket (FP) and one flagellum (*), and of 24 h induced TbCFAP44RNAi (p, s) and TbCFAP43RNAi (q, t) cells. s and t are enlargements of p and q, respectively. Scale bars=100 nm in o–q; 200 nm in r–t. Note: in TbCFAP44RNAi and TbCFAP43RNAi cells, the flagellar pocket is enlarged and bears more than two flagella (p, q). Some of these flagella present axonemal defects including displaced and rotated CPC and shifted DMTs (p, white arrows, s, t)
Fig. 8 T. brucei CFAP44 and CFAP43 are necessary for cell survival and proper axonemal organization. a–d Immunofluorescence on detergent-extracted cells of parental T. brucei stained with anti-PFR (red) and anti-myc (green) antibodies. e–h Immunofluorescence on detergent-extracted cells expressing TbCFAP44myc and RNAi induced (24 h) for TbCFAP44 (TbCFAP44mycRNAi). Cells showed no or weak myc labeling (green) on the new flagellum (NF), while the old flagellum (OF) remained labeled. PFR is labeled in red. Note: cells with a maximum of two flagella were chosen for clear imaging. i–l Similar RNAi experiments as performed in e–h for TbCFAP43 RNAi in cells expressing TbCFAP43myc (TbCFAP43mycRNAi). Cells showed no or weak myc labeling (green) on the new flagellum (NF), while the old flagellum (OF) remained labeled. PFR is labeled in red. Nuclei and kinetoplasts (mitochondrial genome) are labeled with DAPI (blue). Scale bars=5 μm. Insets are enlargement of images of flagella taken from the main panels and display areas indicated by white arrows (scale bar=1 µm). m Growth curves for parental cells, and TbCFAP44RNAi and TbCFAP43RNAi cells, non-induced or induced with tetracycline. The graph represents the cumulative number of cells per ml. Error bars represent the standard error from three independent experiments. n Flagellum length measurement of the new flagellum in cells bearing two flagella from parental cells, and from cells expressing TbCFAP44myc and TbCFAP44myc and induced (24 h) for TbCFAP44 RNAi and TbCFAP43 RNAi, respectively. Flagellum length was measured in cells showing a clear decrease in myc labeling in the new flagellum. o–t Electron micrographs of stained thin sections of parental cells (o, r) bearing one flagellar pocket (FP) and one flagellum (*), and of 24 h induced TbCFAP44RNAi (p, s) and TbCFAP43RNAi (q, t) cells. s and t are enlargements of p and q, respectively. Scale bars=100 nm in o–q; 200 nm in r–t. Note: in TbCFAP44RNAi and TbCFAP43RNAi cells, the flagellar pocket is enlarged and bears more than two flagella (p, q). Some of these flagella present axonemal defects including displaced and rotated CPC and shifted DMTs (p, white arrows, s, t)CC BY · PubMed Central

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  1. Coutton, C., Escoffier, J., Martinez, G., Arnoult, C. & Ray, P. F. Teratozoospermia: spotlight on the main genetic actors in the human. Hum. Reprod. Update 21, 455–485 (2015). · DOI · Paper page

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Authors
Coutton, C., Vargas, A. S., Amiri-Yekta, A., Kherraf, Z.-E., Ben Mustapha, S. F., Le Tanno, P., Wambergue-Legrand, C., Karaouzène, T., Martinez, G., Crouzy, S., Daneshipour, A., Hosseini, S. H., Mitchell, V., Halouani, L., Marrakchi, O., Makni, M., Latrous, H., Kharouf, M., Deleuze, J.-F., Boland, A., Hennebicq, S., Satre, V., Jouk, P.-S., Thierry-Mieg, N., Conne, B., Dacheux, D., Landrein, N., Schmitt, A., Stouvenel, L., Lorès, P., El Khouri, E., Bottari, S. P., Fauré, J., Wolf, J.-P., Pernet-Gallay, K., Escoffier, J., Gourabi, H., Robinson, D. R., Nef, S., Dulioust, E., Zouari, R., Bonhivers, M., Touré, A., Arnoult, C., & Ray, P. F.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Royan Institute (IR)
  • Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
  • Centre Hospitalier Universitaire de Grenoble (FR)
  • Inserm (FR)
  • Sorbonne Paris Cité (FR)
  • University of Geneva (CH)
Corresponding author
Ray, Pierre F.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-02-15
Volume
9
Issue
1
Pages
686-686
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-02792-7
PMC
PMC5814398
OpenAlex
W2806261901
Cited by
245
References
63
Citations by year
2026: 22 · 2025: 19 · 2024: 30 · 2023: 34 · 2022: 35 · 2021: 27 · 2020: 31 · 2019: 29 · 2018: 18
FWCI
28.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
  • HAL (submittedVersion, cc-by)
  • Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
  • Greater South Information System
Funders
  • Fondation Maladies Rares
  • University of Oxford
  • Agence Nationale de la Recherche (ANR-15-CE17-0008, 10-INBS-04, ANR‐10_INBS‐04, ANR-11-LABX-0024, ANR-10, ANR-10-INBS-0004, ANR-14-CE15-0002)
  • Institut National de la Santé et de la Recherche Médicale (ANR-10-INBS-04)
  • Centre National de la Recherche Scientifique (ANR-10-INBS-04)
  • Université de Genève
  • Direction Générale de l’offre de Soins (PRTS 2014)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
Keywords
DNAH1, male infertility, axoneme, paraflagellar rod, doublet microtubules, spermatogenesis, Trypanosoma brucei, axonemal proteins, CRISPR/Cas9 mouse model
MeSH terms
Exome Sequencing, Adult, Animals, Cytoskeletal Proteins, Fertility, Flagella, Homozygote, Humans, Infertility, Male, Male, Microtubule Proteins, Middle Aged, Mutation, Nuclear Proteins, Peptide Hydrolases, Sperm Motility, Spermatozoa, Trypanosoma, Cohort Studies, Microscopy, Immunoelectron, Mice, Knockout, Mice, Axoneme, Clustered Regularly Interspaced Short Palindromic Repeats

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