Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes

被引：213

作者：

Valente, Enza Maria ^{[2
,3
]}

Logan, Clare V. ^{[4
]}

Mougou-Zerelli, Soumaya ^{[5
,6
]}

Lee, Jeong Ho ^{[1
]}

Silhavy, Jennifer L. ^{[1
]}

Brancati, Francesco ^{[2
,7
,8
]}

Iannicelli, Miriam ^{[2
]}

Travaglini, Lorena ^{[2
]}

Romani, Sveva ^{[2
]}

Illi, Barbara ^{[2
]}

Adams, Matthew ^{[4
]}

Szymanska, Katarzyna ^{[4
]}

Mazzotta, Annalisa ^{[2
]}

Lee, Ji Eun ^{[1
]}

Tolentino, Jerlyn C. ^{[1
]}

Swistun, Dominika ^{[1
]}

Salpietro, Carmelo D. ^{[3
]}

Fede, Carmelo ^{[3
]}

Gabriel, Stacey ^{[9
]}

Russ, Carsten ^{[9
]}

Cibulskis, Kristian ^{[9
]}

Sougnez, Carrie ^{[9
]}

Hildebrandt, Friedhelm ^{[10
]}

Otto, Edgar A. ^{[10
]}

Held, Susanne ^{[10
]}

Diplas, Bill H. ^{[11
]}

Davis, Erica E. ^{[11
]}

Mikula, Mario ^{[12
]}

Strom, Charles M. ^{[12
]}

Ben-Zeev, Bruria ^{[13
]}

Lev, Dorit ^{[14
]}

Sagie, Tally Lerman ^{[14
]}

Michelson, Marina ^{[14
]}

Yaron, Yuval ^{[15
]}

Krause, Amanda ^{[16
]}

Boltshauser, Eugen ^{[17
]}

Elkhartoufi, Nadia ^{[18
]}

Roume, Joelle ^{[19
]}

Shalev, Stavit ^{[20
]}

Munnich, Arnold ^{[5
,18
]}

Saunier, Sophie ^{[21
]}

Inglehearn, Chris ^{[4
]}

Saad, Ali ^{[6
]}

Alkindy, Adila ^{[22
]}

Thomas, Sophie ^{[5
]}

Vekemans, Michel ^{[5
,18
]}

Dallapiccola, Bruno ^{[23
]}

Katsanis, Nicholas ^{[11
]}

Johnson, Colin A. ^{[4
]}

Attie-Bitach, Tania ^{[5
,18
]}

机构：

[1] Univ Calif San Diego, Howard Hughes Med Inst, Dept Neurosci & Pediat, Inst Genom Med,Neurogenet Lab, San Diego, CA 92103 USA

[2] Ist Ricovero Cura Carattere Sci Casa Sollievo Sof, Mendel Lab, San Giovanni Rotondo, Italy

[3] Univ Messina, Dept Med & Surg Paediat Sci, Messina, Italy

[4] St James Univ Hosp, Leeds Inst Mol Med, Sect Ophthalmol & Neurosci, Leeds, W Yorkshire, England

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

[6] Hop Farhat Hached, Serv Cytogenet Genet Mol & Biol Reprod, Sousse, Tunisia

[7] Univ G dAnnunzio, Ctr Excellence Aging, Dept Biomed Sci, Chieti, Italy

[8] Univ G dAnnunzio, Ctr Excellence Aging, Aging Res Ctr, Chieti, Italy

[9] Broad Inst, Genome Sequencing & Anal Program, Cambridge, MA USA

[10] Univ Michigan, Howard Hughes Med Inst, Dept Pediat, Ann Arbor, MI 48109 USA

[11] Duke Univ, Ctr Human Dis Modeling, Durham, NC USA

[12] Quest Diagnost Nichols Inst, San Juan Capistrano, CA USA

[13] Safra Pediat Hosp, Sheba Med Ctr, Pediat Neurol Unit, Ramat Gan, Israel

[14] Wolfson Med Ctr, Metab Neurogenet Serv, Inst Med Genet, Holon, Israel

[15] Tel Aviv Sourasky Med Ctr, Genet Inst, Prenatal Diag Unit, Tel Aviv, Israel

[16] Univ Witwatersrand, Sch Pathol, Natl Hlth Lab Serv, Div Human Genet, Johannesburg, South Africa

[17] Univ Childrens Hosp Zurich, Dept Paediat Neurol, Zurich, Switzerland

[18] Hop Necker Enfants Malad, AP HP, Dept Genet, Paris, France

[19] CHI Poissy, St Germain En Laye, France

[20] HaEmek Med Ctr, Genet Inst, Afula, Israel

[21] Univ Paris 05, Hop Necker Enfants Malad, AP HP, INSERM,U983, Paris, France

[22] Univ Wales Hosp, Cardiff CF4 4XW, S Glam, Wales

[23] Ist Ricovero & Cura Carattere Sci Bambino Gesu Ho, Rome, Italy

来源：

NATURE GENETICS | 2010年 / 42卷 / 07期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

BARDET-BIEDL-SYNDROME; PLANAR CELL POLARITY; GRUBER-SYNDROME; ACTIN CYTOSKELETON; RENAL SYNDROME; GENE; PROTEINS; CILIARY; DISSECTION; MECHANISMS;

D O I：

10.1038/ng.594

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Joubert syndrome (JBTS), related disorders (JSRDs) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n = 10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.

引用

页码：619 / U100

页数：9

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