CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium

被引：144

作者：

Lee, Ji Eun ^{[1
,2
]}

Silhavy, Jennifer L. ^{[1
,2
]}

Zaki, Maha S. ^{[3
]}

Schroth, Jana ^{[1
,2
]}

Bielas, Stephanie L. ^{[1
,2
]}

Marsh, Sarah E. ^{[1
,2
]}

Olvera, Jesus ^{[1
,2
]}

Brancati, Francesco ^{[4
,5
]}

Iannicelli, Miriam ^{[4
]}

Ikegami, Koji ^{[6
]}

Schlossman, Andrew M. ^{[1
,2
]}

Merriman, Barry ^{[7
]}

Attie-Bitach, Tania ^{[8
]}

Logan, Clare V. ^{[9
]}

Glass, Ian A. ^{[10
,11
]}

Cluckey, Andrew ^{[12
]}

Louie, Carrie M. ^{[1
,2
]}

Lee, Jeong Ho ^{[1
,2
]}

Raynes, Hilary R. ^{[13
,14
,15
]}

Rapin, Isabelle ^{[13
,14
,15
]}

Castroviejo, Ignacio P. ^{[16
]}

Setou, Mitsutoshi ^{[6
]}

Barbot, Clara ^{[17
]}

Boltshauser, Eugen ^{[18
]}

Nelson, Stanley F. ^{[7
]}

Hildebrandt, Friedhelm ^{[12
]}

Johnson, Colin A. ^{[9
]}

Doherty, Daniel A. ^{[10
,11
]}

Valente, Enza Maria ^{[4
,19
]}

Gleeson, Joseph G. ^{[1
,2
]}

机构：

[1] Univ Calif San Diego, Dept Neurosci, Howard Hughes Med Inst, San Diego, CA 92103 USA

[2] Univ Calif San Diego, Dept Pediat, Inst Genom Med, Neurogenet Lab, San Diego, CA 92103 USA

[3] Natl Res Ctr, Human Genet & Genome Res Div, Dept Clin Genet, Dokki, Egypt

[4] Casa Sollievo Sofferenza CSS Hosp, CSS Mendel Lab, San Giovanni Rotondo, Italy

[5] Tor Vergata Univ, Dept Biopathol & Diagnost Imaging, Med Genet Unit, Rome, Italy

[6] Hamamatsu Univ Sch Med, Dept Cell Biol & Anat, Hamamatsu, Shizuoka 4313192, Japan

[7] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet Pathol & Lab Med, Los Angeles, CA 90095 USA

[8] Univ Paris 05, Hop Necker Enfants Malad, Dept Genet, INSERM,U781, Paris, France

[9] St James Univ Hosp, Leeds Inst Mol Med, Sect Ophthalmol & Neurosci, Leeds LS9 7TF, W Yorkshire, England

[10] Univ Washington, Dept Pediat, Div Dev Med, Seattle Childrens Hosp, Seattle, WA 98195 USA

[11] Univ Washington, Div Med Genet, Seattle Childrens Hosp, Seattle, WA 98195 USA

[12] Univ Michigan, Howard Hughes Med Inst, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA

[13] Albert Einstein Coll Med, Saul R Korey Dept Neurol, New York, NY USA

[14] Albert Einstein Coll Med, Dept Pediat, New York, NY USA

[15] Albert Einstein Coll Med, Rose F Kennedy Intellectual & Dev Disabil Res Ctr, New York, NY USA

[16] Univ Hosp La Paz, Pediat Neurol Serv, Madrid, Spain

[17] Hosp Criancas Maria Pia, Serv Neuropediat, Oporto, Portugal

[18] Univ Childrens Hosp Zurich, Dept Pediat Neurol, Zurich, Switzerland

[19] Univ Messina, Dept Med & Surg Pediat Sci, Messina, Italy

来源：

NATURE GENETICS | 2012年 / 44卷 / 02期

基金：

美国国家卫生研究院; 日本学术振兴会; 英国医学研究理事会;

关键词：

LEFT-RIGHT ASYMMETRY; PLANAR CELL POLARITY; POSTTRANSLATIONAL MODIFICATIONS; CILIARY MOTILITY; PROTEIN; POLYGLUTAMYLATION; ZEBRAFISH; CILIOGENESIS; POLYGLYCYLATION; CILIOPATHIES;

D O I：

10.1038/ng.1078

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function(1,2). However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (IBTS)(3), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein(4). We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme(5). Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.

引用

页码：193 / 199

页数：7

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