Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization

被引：77

作者：

Bizet, Albane A. ^{[1
,2
]}

Becker-Heck, Anita

Ryan, Rebecca ^{[1
,2
]}

Weber, Kristina ^{[3
]}

Filhol, Emilie ^{[1
,2
]}

Krug, Pauline ^{[1
,2
]}

Halbritter, Jan ^{[4
,5
,6
]}

Delous, Marion ^{[1
,2
]}

Lasbennes, Marie-Christine

Linghu, Bolan ^{[7
]}

Oakeley, Edward J.

Zarhrate, Mohammed ^{[2
,8
]}

Nitschke, Patrick ^{[2
,9
]}

Garfa-Traore, Meriem ^{[10
]}

Serluca, Fabrizio ^{[7
]}

Yang, Fan ^{[7
]}

Bouwmeester, Tewis

Pinson, Lucile ^{[11
]}

Cassuto, Elisabeth ^{[12
]}

Dubot, Philippe ^{[13
]}

Elshakhs, Neveen A. Soliman ^{[14
]}

Sahel, Jose A. ^{[15
,16
]}

Salomon, Remi ^{[1
,2
,17
]}

Drummond, Iain A. ^{[18
,19
]}

Gubler, Marie-Claire ^{[1
,2
]}

Antignac, Corinne ^{[1
,2
,20
]}

Chibout, Salandine

Szustakowski, Joseph D. ^{[7
]}

Hildebrandt, Friedhelm ^{[4
,5
]}

Lorentzen, Esben ^{[3
]}

Sailer, Andreas W.

Benmerah, Alexandre ^{[1
,2
]}

Saint-Mezard, Pierre

Saunier, Sophie ^{[1
,2
]}

机构：

[1] Inserm UMR 1163, Lab Hereditary Kidney Dis, F-75015 Paris, France

[2] Paris Descartes Sorbonne Paris Cite Univ, Imagine Inst, F-75015 Paris, France

[3] Max Planck Inst Biochem, Dept Struct Cell Biol, D-82152 Martinsried, Germany

[4] Boston Childrens Hosp, Dept Med, Div Nephrol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Boston, MA 02115 USA

[6] Univ Clin Leipzig, Dept Internal Med, Div Nephrol, D-04103 Leipzig, Germany

[7] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[8] Inserm UMR 1163, Genom Core Facil, F-75015 Paris, France

[9] Paris Descartes Sorbonne Paris Cite Univ, Bioinformat Core Facil, F-75015 Paris, France

[10] Paris Descartes Sorbonne Paris Cite Univ, Cell Imaging Platform, INSERM Struct Federat Rech Necker US24, F-75015 Paris, France

[11] Arnaud de Villeneuve Univ Hlth Ctr, Dept Med Genet, F-34090 Montpellier, France

[12] Univ Nice, Ctr Hlth, LArchet Hosp 2, Dept Nephrol, F-06202 Nice, France

[13] William Morey Hosp, Hemodialysis Nephrol Dept, F-71321 Chalon Sur Saone, France

[14] Cairo Univ, Egyptian Grp Orphan Renal Dis, Dept Pediat, Ctr Pediat Nephrol & Transplantat, Cairo 11956, Egypt

[15] Univ Paris 06, INSERM U968, CNRS UMR 7210, Sorbonne Univ,UMR S968,Inst Vis, F-75012 Paris, France

[16] Ctr Hosp Natl Ophtalmol Quinze Vingts, INSERM, Direct Hosp & Org Soins, Ctr Invest Clin 1423, F-75012 Paris, France

[17] Necker Enfants Malad Hosp, AP HP, Pediat Nephrol Dept, F-75015 Paris, France

[18] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02114 USA

[19] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA

[20] Necker Enfants Malad Hosp, AP HP, Dept Genet, F-75015 Paris, France

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

CILIARY; COMPLEX; CILIOGENESIS; CILIOPATHY; TRANSPORT; POLARITY; DEFECTS; NEPHRONOPHTHISIS; NEPHROCYSTIN-4; STABILITY;

D O I：

10.1038/ncomms9666

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：

Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies.

引用

页数：14

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