title: TCTN3 mutations cause Mohr-Majewski syndrome.
abstract: Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and one homozygous missense mutation in a family with Joubert syndrome. By exploring roles of TCTN3 in human ciliary related functions, we found that TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. These results are consistent with the suggested role of its murine ortholog, which forms a complex at the ciliary transition zone with TCTN1 and TCTN2, both of which are also implicated in the transduction of SHH signaling. Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes.
authors.affiliation: INSERM U781, Hôpital Necker-Enfants Malades, 75015 Paris, France; Université Paris Descartes, 75006 Paris Sorbonne, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.forename: Marine
authors.initials: M
authors.lastname: Legendre
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
authors.forename: Bettina
authors.initials: B
authors.lastname: Bessières
authors.forename: Caroline
authors.initials: C
authors.lastname: Alby
authors.forename: Maryse
authors.initials: M
authors.lastname: Bonnière
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.forename: Laurence
authors.initials: L
authors.lastname: Loeuillet
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Szymanska
authors.forename: Frédérique
authors.initials: F
authors.lastname: Jossic
authors.forename: Dominique
authors.initials: D
authors.lastname: Gaillard
authors.forename: Mohamed Tahar
authors.initials: MT
authors.lastname: Yacoubi
authors.forename: Soumaya
authors.initials: S
authors.lastname: Mougou-Zerelli
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Barthez
authors.forename: Yves
authors.initials: Y
authors.lastname: Ville
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Férechté
authors.initials: F
authors.lastname: Encha-Razavi
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002531:Cerebellum / Q000002:abnormalities / Q000473:pathology; D002648:Child; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005333:Fetus / Q000473:pathology; D005532:Foot Deformities, Congenital / Q000235:genetics* / Q000473:pathology; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009958:Orofaciodigital Syndromes / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C575748:TCTN3 protein, human