Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes.
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.
Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. e.valente@css-mendel.it
Enza Maria
EM
Valente
Clare V
CV
Logan
Soumaya
S
Mougou-Zerelli
Jeong Ho
JH
Lee
Jennifer L
JL
Silhavy
Francesco
F
Brancati
Miriam
M
Iannicelli
Lorena
L
Travaglini
Sveva
S
Romani
Barbara
B
Illi
Matthew
M
Adams
Katarzyna
K
Szymanska
Annalisa
A
Mazzotta
Ji Eun
JE
Lee
Jerlyn C
JC
Tolentino
Dominika
D
Swistun
Carmelo D
CD
Salpietro
Carmelo
C
Fede
Stacey
S
Gabriel
Carsten
C
Russ
Kristian
K
Cibulskis
Carrie
C
Sougnez
Friedhelm
F
Hildebrandt
Edgar A
EA
Otto
Susanne
S
Held
Bill H
BH
Diplas
Erica E
EE
Davis
Mario
M
Mikula
Charles M
CM
Strom
Bruria
B
Ben-Zeev
Dorit
D
Lev
Tally Lerman
TL
Sagie
Marina
M
Michelson
Yuval
Y
Yaron
Amanda
A
Krause
Eugen
E
Boltshauser
Nadia
N
Elkhartoufi
Joelle
J
Roume
Stavit
S
Shalev
Arnold
A
Munnich
Sophie
S
Saunier
Chris
C
Inglehearn
Ali
A
Saad
Adila
A
Alkindy
Sophie
S
Thomas
Michel
M
Vekemans
Bruno
B
Dallapiccola
Nicholas
N
Katsanis
Colin A
CA
Johnson
Tania
T
Attié-Bitach
Joseph G
JG
Gleeson
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002923:Cilia / Q000473:pathology*; D003241:Consanguinity; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D054262:Gastrulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007585:Jews / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D013577:Syndrome; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
D008565:Membrane Proteins; C551542:TMEM216 protein, human; D049452:Green Fluorescent Proteins