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

Enza Maria Valente; Clare V. Logan; Soumaya Mougou-Zerelli; Jeong Ho Lee; Jennifer L. Silhavy; Francesco Brancati; Miriam Iannicelli; Lorena Travaglini; Sveva Romani; Barbara Illi; Matthew Adams; Katarzyna Szymanska; Annalisa Mazzotta; Ji Eun Lee; Jerlyn C. Tolentino; Dominika Swistun; Carmelo D. Salpietro; Carmelo Fede; Stacey Gabriel; Carsten Russ; Kristian Cibulskis; Carrie Sougnez; Friedhelm Hildebrandt; Edgar A. Otto; Susanne Held; Bill H. Diplas; Erica E. Davis; Mario Mikula; Charles M. Strom; Bruria Ben-Zeev; Dorit Lev; Tally Lerman Sagie; Marina Michelson; Yuval Yaron; Amanda Krause; Eugen Boltshauser; Nadia Elkhartoufi; Joelle Roume; Stavit Shalev; Arnold Munnich; Sophie Saunier; Chris Inglehearn; Ali Saad; Adila Alkindy; Sophie Thomas; Michel Vekemans; Bruno Dallapiccola; Nicholas Katsanis; Colin A. Johnson; Tania Attié-Bitach; Joseph G. Gleeson

doi:10.1038/ng.594

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

Enza Maria Valente
, Clare V. Logan
, Soumaya Mougou-Zerelli
, Jeong Ho Lee
, Jennifer L. Silhavy
, Francesco Brancati
, Miriam Iannicelli
, Lorena Travaglini
, Sveva Romani
, Barbara Illi
, Matthew Adams
, Katarzyna Szymanska
, Annalisa Mazzotta
, Ji Eun Lee
, Jerlyn C. Tolentino
, Dominika Swistun
, Carmelo D. Salpietro
, Carmelo Fede
, Stacey Gabriel
, Carsten Russ

Kristian Cibulskis, Carrie Sougnez, Friedhelm Hildebrandt, Edgar A. Otto, Susanne Held, Bill H. Diplas, Erica E. Davis, Mario Mikula, Charles M. Strom, Bruria Ben-Zeev, Dorit Lev, Tally Lerman Sagie, Marina Michelson, Yuval Yaron, Amanda Krause, Eugen Boltshauser, Nadia Elkhartoufi, Joelle Roume, Stavit Shalev, Arnold Munnich, Sophie Saunier, Chris Inglehearn, Ali Saad, Adila Alkindy, Sophie Thomas, Michel Vekemans, Bruno Dallapiccola, Nicholas Katsanis, Colin A. Johnson, Tania Attié-Bitach, Joseph G. Gleeson

IRCCS Ospedale Casa Sollievo della Sofferenza - San Giovanni Rotondo (FG)
University of Messina
Leeds Teaching Hospitals NHS Trust
Université Paris Cité
University of Sousse
University of California at San Diego
Gabriele d'Annunzio University
Broad Institute
University of Michigan, Ann Arbor
Duke University
Quest Diagnostics Incorporated
Sheba Medical Center at Tel Hashomer
Edith Wolfson Medical Center Israel
Tel Aviv Sourasky Medical Center
University of the Witwatersrand
University of Zurich
CHI de Poissy-St-Germain-en-Laye
Emek Medical Center
Institut national de la santé et de la recherche médicale
Cardiff & Vale University Health Board
Sultan Qaboos University
IRCCS Ospedale pediatrico Bambino Gesù - Roma

Research output: Contribution to journal › Article › peer-review

256 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	619-625
Number of pages	7
Journal	Nature Genetics
Volume	42
Issue number	7
DOIs	https://doi.org/10.1038/ng.594
State	Published - Jul 2010
Externally published	Yes

Funding

Funders	Funder number
Agence Nationale de la Recherche
Broad Institute
Sir Jules Thorn Charitable Trust
US National Institutes of Health National Heart, Lung, and Blood Institute
l’Agence National pour la Recherche
Burroughs Wellcome Fund
Marshfield Clinic Research Foundation
Fondazione Pierfranco e Luisa Mariani
BDF Newlife
Howard Hughes Medical Institute
UK Research and Innovation
National Institute of General Medical Sciences	R01GM121317
Ministero della Salute	RC2010
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK072301, F32DK079541, R01DK075972, R01DK068306
National Institute of Neurological Disorders and Stroke	R01NS052455, R01NS048453, P30NS047101
National Institutes of Health	R01 HD04260, R01 NS04843
Medical Research Council	G0700073
INSERM-DGRSRT	87
National Human Genome Research Institute	U54HG003067
Fondazione Telethon	GGP08145
American Heart Association	O9POST2250641
Eunice Kennedy Shriver National Institute of Child Health and Human Development	R01HD042601

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10.1038/ng.594

Cite this

Valente, E. M., Logan, C. V., Mougou-Zerelli, S., Lee, J. H., Silhavy, J. L., Brancati, F., Iannicelli, M., Travaglini, L., Romani, S., Illi, B., Adams, M., Szymanska, K., Mazzotta, A., Lee, J. E., Tolentino, J. C., Swistun, D., Salpietro, C. D., Fede, C., Gabriel, S., ... Gleeson, J. G. (2010). Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nature Genetics, 42(7), 619-625. https://doi.org/10.1038/ng.594

@article{0d72e46e3efb4216bed8333660667113,

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

abstract = "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.",

author = "Valente, \{Enza Maria\} and Logan, \{Clare V.\} and Soumaya Mougou-Zerelli and Lee, \{Jeong Ho\} and Silhavy, \{Jennifer L.\} and Francesco Brancati and Miriam Iannicelli and Lorena Travaglini and Sveva Romani and Barbara Illi and Matthew Adams and Katarzyna Szymanska and Annalisa Mazzotta and Lee, \{Ji Eun\} and Tolentino, \{Jerlyn C.\} and Dominika Swistun and Salpietro, \{Carmelo D.\} and Carmelo Fede and Stacey Gabriel and Carsten Russ and Kristian Cibulskis and Carrie Sougnez and Friedhelm Hildebrandt and Otto, \{Edgar A.\} and Susanne Held and Diplas, \{Bill H.\} and Davis, \{Erica E.\} and Mario Mikula and Strom, \{Charles M.\} and Bruria Ben-Zeev and Dorit Lev and Sagie, \{Tally Lerman\} and Marina Michelson and Yuval Yaron and Amanda Krause and Eugen Boltshauser and Nadia Elkhartoufi and Joelle Roume and Stavit Shalev and Arnold Munnich and Sophie Saunier and Chris Inglehearn and Ali Saad and Adila Alkindy and Sophie Thomas and Michel Vekemans and Bruno Dallapiccola and Nicholas Katsanis and Johnson, \{Colin A.\} and Tania Atti{\'e}-Bitach and Gleeson, \{Joseph G.\}",

note = "Funding Information: We thank Marshfield Clinic Research Foundation, Center for Inherited Disease Research (supported by the US National Institutes of Health National Heart, Lung, and Blood Institute) for genotyping support and A. Felsenfeld and the Medical Sequencing Initiative at the National Human Genome Research Institute. We acknowledge support for sequencing from the Broad Institute and the Broad Sequencing Platform and J. Meerloo at the University of California, San Diego Neurosciences Microscopy Core (Supported by National Institute of Neurological Disorders and Stroke grant P30NS047101). For patient referrals, we thank C. Jalas at Bonei Olam Center for Rare Jewish Genetic Disorders; M.R. Eccles at the University of Otago; H.M. Harville at University of Michigan; G. Tortorella, S. Briuglia, R. Chimenz, R. Gallizzi and M. Briguglio at University of Messina; E. Bertini and the International JSRD Study Group; and the French Society of Foetal Pathology. We thank E. Morrison, P. Novick and S. Ferro-Novick for helpful discussions; C. Janke (Macromolecular Biochemistry Research Center) for GT335 antibody; P. Robinson (University of Leeds) for siRNA duplexes against Hhari; E. Genin for linkage analysis, S. Audolent, C. Babarit, F. Legendre and H.-M. Gaud{\'e} for technical help and O. Duc for confocal microscopy. S.M.-Z. is supported by INSERM-DGRSRT (CS/RN/2008 no. 87). This work was supported by the Italian Ministry of Health (RC2010, Ricerca Finalizzata 2006), Telethon Foundation Italy (GGP08145 to E.M.V.), Pierfranco and Luisa Mariani Foundation (E.M.V.), American Heart Association grant O9POST2250641 (J.E.L.), BDF Newlife, the Medical Research Council (G0700073) and the Sir Jules Thorn Charitable Trust (09/JTA to C.A.J.), l{\textquoteright}Agence National pour la Recherche (ANR 07-MRAR-Fetalciliopathies to T.A.-B.), the US National Institutes of Health (R01 DK068306 to F.H.; R01 DK072301, R01 HD04260 and R01 DK075972 to N.K.; National Research Service Award fellowship F32 DK079541 to E.E.D., R01 NS052455 and R01 NS04843 to J.G.G.), Burroughs Wellcome Fund and Howard Hughes Medical Institute (F.H. and J.G.G.).",

year = "2010",

month = jul,

doi = "10.1038/ng.594",

language = "אנגלית",

volume = "42",

pages = "619--625",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "7",

}

Valente, EM, Logan, CV, Mougou-Zerelli, S, Lee, JH, Silhavy, JL, Brancati, F, Iannicelli, M, Travaglini, L, Romani, S, Illi, B, Adams, M, Szymanska, K, Mazzotta, A, Lee, JE, Tolentino, JC, Swistun, D, Salpietro, CD, Fede, C, Gabriel, S, Russ, C, Cibulskis, K, Sougnez, C, Hildebrandt, F, Otto, EA, Held, S, Diplas, BH, Davis, EE, Mikula, M, Strom, CM, Ben-Zeev, B , Lev, D , Sagie, TL, Michelson, M, Yaron, Y, Krause, A, Boltshauser, E, Elkhartoufi, N, Roume, J, Shalev, S, Munnich, A, Saunier, S, Inglehearn, C, Saad, A, Alkindy, A, Thomas, S, Vekemans, M, Dallapiccola, B, Katsanis, N, Johnson, CA, Attié-Bitach, T & Gleeson, JG 2010, 'Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes', Nature Genetics, vol. 42, no. 7, pp. 619-625. https://doi.org/10.1038/ng.594

TY - JOUR

T1 - Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes

AU - Valente, Enza Maria

AU - Logan, Clare V.

AU - Mougou-Zerelli, Soumaya

AU - Lee, Jeong Ho

AU - Silhavy, Jennifer L.

AU - Brancati, Francesco

AU - Iannicelli, Miriam

AU - Travaglini, Lorena

AU - Romani, Sveva

AU - Illi, Barbara

AU - Adams, Matthew

AU - Szymanska, Katarzyna

AU - Mazzotta, Annalisa

AU - Lee, Ji Eun

AU - Tolentino, Jerlyn C.

AU - Swistun, Dominika

AU - Salpietro, Carmelo D.

AU - Fede, Carmelo

AU - Gabriel, Stacey

AU - Russ, Carsten

AU - Cibulskis, Kristian

AU - Sougnez, Carrie

AU - Hildebrandt, Friedhelm

AU - Otto, Edgar A.

AU - Held, Susanne

AU - Diplas, Bill H.

AU - Davis, Erica E.

AU - Mikula, Mario

AU - Strom, Charles M.

AU - Ben-Zeev, Bruria

AU - Lev, Dorit

AU - Sagie, Tally Lerman

AU - Michelson, Marina

AU - Yaron, Yuval

AU - Krause, Amanda

AU - Boltshauser, Eugen

AU - Elkhartoufi, Nadia

AU - Roume, Joelle

AU - Shalev, Stavit

AU - Munnich, Arnold

AU - Saunier, Sophie

AU - Inglehearn, Chris

AU - Saad, Ali

AU - Alkindy, Adila

AU - Thomas, Sophie

AU - Vekemans, Michel

AU - Dallapiccola, Bruno

AU - Katsanis, Nicholas

AU - Johnson, Colin A.

AU - Attié-Bitach, Tania

AU - Gleeson, Joseph G.

N1 - Funding Information: We thank Marshfield Clinic Research Foundation, Center for Inherited Disease Research (supported by the US National Institutes of Health National Heart, Lung, and Blood Institute) for genotyping support and A. Felsenfeld and the Medical Sequencing Initiative at the National Human Genome Research Institute. We acknowledge support for sequencing from the Broad Institute and the Broad Sequencing Platform and J. Meerloo at the University of California, San Diego Neurosciences Microscopy Core (Supported by National Institute of Neurological Disorders and Stroke grant P30NS047101). For patient referrals, we thank C. Jalas at Bonei Olam Center for Rare Jewish Genetic Disorders; M.R. Eccles at the University of Otago; H.M. Harville at University of Michigan; G. Tortorella, S. Briuglia, R. Chimenz, R. Gallizzi and M. Briguglio at University of Messina; E. Bertini and the International JSRD Study Group; and the French Society of Foetal Pathology. We thank E. Morrison, P. Novick and S. Ferro-Novick for helpful discussions; C. Janke (Macromolecular Biochemistry Research Center) for GT335 antibody; P. Robinson (University of Leeds) for siRNA duplexes against Hhari; E. Genin for linkage analysis, S. Audolent, C. Babarit, F. Legendre and H.-M. Gaudé for technical help and O. Duc for confocal microscopy. S.M.-Z. is supported by INSERM-DGRSRT (CS/RN/2008 no. 87). This work was supported by the Italian Ministry of Health (RC2010, Ricerca Finalizzata 2006), Telethon Foundation Italy (GGP08145 to E.M.V.), Pierfranco and Luisa Mariani Foundation (E.M.V.), American Heart Association grant O9POST2250641 (J.E.L.), BDF Newlife, the Medical Research Council (G0700073) and the Sir Jules Thorn Charitable Trust (09/JTA to C.A.J.), l’Agence National pour la Recherche (ANR 07-MRAR-Fetalciliopathies to T.A.-B.), the US National Institutes of Health (R01 DK068306 to F.H.; R01 DK072301, R01 HD04260 and R01 DK075972 to N.K.; National Research Service Award fellowship F32 DK079541 to E.E.D., R01 NS052455 and R01 NS04843 to J.G.G.), Burroughs Wellcome Fund and Howard Hughes Medical Institute (F.H. and J.G.G.).

PY - 2010/7

Y1 - 2010/7

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/77954144620

U2 - 10.1038/ng.594

DO - 10.1038/ng.594

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 20512146

AN - SCOPUS:77954144620

SN - 1061-4036

VL - 42

SP - 619

EP - 625

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

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

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