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

被引：185

作者：

Coutton, Charles ^{[1
,2
]}

Vargas, Alexandra S. ^{[1
]}

Amiri-Yekta, Amir ^{[1
,3
,4
]}

Kherraf, Zine-Eddine ^{[1
,3
]}

Ben Mustapha, Selima Fourati ^{[5
]}

Le Tanno, Pauline ^{[1
,2
]}

Wambergue-Legrand, Clementine ^{[1
,3
]}

Karaouzene, Thomas ^{[1
,3
]}

Martinez, Guillaume ^{[1
,2
]}

Crouzy, Serge ^{[6
]}

Daneshipour, Abbas ^{[4
]}

Hosseini, Seyedeh Hanieh ^{[7
]}

Mitchell, Valerie ^{[8
]}

Halouani, Lazhar ^{[5
]}

Marrakchi, Ouafi ^{[5
]}

Makni, Mounir ^{[5
]}

Latrous, Habib ^{[5
]}

Kharouf, Mahmoud ^{[5
]}

Deleuze, Jean-Francois ^{[9
]}

Boland, Anne ^{[9
]}

Hennebicq, Sylviane ^{[1
,10
]}

Satre, Veronique ^{[1
,2
]}

Jouk, Pierre-Simon ^{[11
]}

Thierry-Mieg, Nicolas ^{[12
]}

Conne, Beatrice ^{[13
]}

Dacheux, Denis ^{[14
,15
]}

Landrein, Nicolas ^{[14
]}

Schmitt, Alain ^{[16
,17
,18
]}

Stouvenel, Laurence ^{[16
,17
,18
]}

Lores, Patrick ^{[16
,17
,18
]}

El Khouri, Elma ^{[16
,17
,18
]}

Bottari, Serge P. ^{[1
]}

Faure, Julien ^{[19
,20
]}

Wolf, Jean-Philippe ^{[18
,21
]}

Pernet-Gallay, Karin ^{[20
]}

Escoffier, Jessica ^{[1
]}

Gourabi, Hamid ^{[4
]}

Robinson, Derrick R. ^{[14
]}

Nef, Serge ^{[13
]}

Dulioust, Emmanuel ^{[18
,21
]}

Zouari, Raoudha ^{[5
]}

Bonhivers, Melanie ^{[14
]}

Toure, Aminata ^{[16
,17
,18
]}

Arnoult, Christophe ^{[1
]}

Ray, Pierre F. ^{[1
,3
]}

机构：

[1] Univ Grenoble Alpes, CNRS UMR 5309, Inserm U1209, Inst Adv Biosci,Genet Epigenet & Therapies Infert, F-38000 Grenoble, France

[2] CHU Grenoble, UM Genet Chromosom, F-38000 Grenoble, France

[3] CHU Grenoble, UM GI DPI, F-38000 Grenoble, France

[4] ACER, Royan Inst Reprod Biomed, Dept Genet, Reprod Biomed Res Ctr, Tehran 16635148, Iran

[5] Ctr Urbain Nord, Ctr Aide Med Procreat, Polyclin Jasmins, Tunis 1003, Tunisia

[6] Univ Grenoble Alpes, CNRS UMR 5249, CEA iRTSV LCBM GMCT, Inst Rech Technol & Sci Vivant,Lab Chim & Biol Me, F-38054 Grenoble, France

[7] ACECR, Royan Inst Reprod Biomed, Dept Androl, Reprod Biomed Res Ctr, Tehran 16635148, Iran

[8] Univ Med Ctr, Dept Reprod Biol & Spermiol CECOS Lille, EA 4308, F-59037 Lille, France

[9] CEA, Inst Genom, Ctr Natl Genotypage, F-91000 Evry, France

[10] CHU Grenoble, UF Biol Procreat, F-38000 Grenoble, France

[11] CHU Grenoble, UF Genet Med, F-38000 Grenoble, France

[12] Univ Grenoble Alpes, CNRS TIMC IMAG, F-38000 Grenoble, France

[13] Univ Geneva, Med Sch, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland

[14] Univ Bordeaux, CNRS UMR 5234, Microbiol Fondamentale & Pathogenicite, F-33000 Bordeaux, France

[15] Bordeaux INP, UMR CNRS 5234, Microbiol Fondamentale & Pathogenicite, F-33000 Bordeaux, France

[16] INSERM, Inst Cochin, U1016, F-75014 Paris, France

[17] CNRS, UMR8104, F-75014 Paris, France

[18] Univ Paris 05, Sorbonne Paris Cite, Fac Med, F-75014 Paris, France

[19] CHU Grenoble, UF Biochim Genet & Mol, F-38000 Grenoble, France

[20] INSERM 1216, Grenoble Neurosci Inst, F-38000 Grenoble, France

[21] GH Cochin Broca Hotel Dieu, AP HP, Lab Histol Embryol Biol Reprod, F-75014 Paris, France

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

MULTIPLE MORPHOLOGICAL ABNORMALITIES; PARAFLAGELLAR ROD; GENETIC-VARIATION; SPERM FLAGELLA; BRUCEI; MOTILITY; PROTEINS; DYNEIN; DNAH1; CILIA;

D O I：

10.1038/s41467-017-02792-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：18

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