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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
TCTN3 mutations cause Mohr-Majewski syndrome
American Journal of Human Genetics, Volume 91, No. 2, Year 2012
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Description
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. © 2012 The American Society of Human Genetics.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3415538/bin/mmc1.pdf
Authors & Co-Authors
Thomas, Sophie
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Legendre, Marine
France, Paris
Hôpital Necker Enfants Malades
Saunier, Sophie
France, Paris
Université Paris Cité
France, Paris
Hôpital Necker Enfants Malades
Bessières, Bettina
France, Paris
Hôpital Necker Enfants Malades
Alby, Caroline
France, Paris
Université Paris Cité
France, Paris
Hôpital Necker Enfants Malades
Bonnière, Maryse
France, Paris
Hôpital Necker Enfants Malades
Toutain, Annick M.
France, Tours
Centre Hospitalier Regional et Universitaire de Tours
Loeuillet, Laurence
France, Poissy
Centre Hospitalier Intercommunal Poissy-st-germain-en-laye
Szymanska, Katarzyna
United Kingdom, Leeds
St James's University Hospital
Jossic, Frédérique
France, Nantes
Chu de Nantes
Gaillard, Dominique A.
France, Reims
Chu de Reims
Yacoubi, Mohamed Tahar
Tunisia, Sousse
Hopital Farhat Hached Sousse
Mougou, S.
Tunisia, Sousse
Hopital Farhat Hached Sousse
David, Albert
France, Nantes
Hôtel Dieu Chu de Nantes
Barthez, Marie Anne
France, Tours
Centre de Pediatrie Clocheville
Ville, Yves H.
France, Paris
Université Paris Cité
France, Paris
Hôpital Necker Enfants Malades
Bôle-Feysot, Christine
France, Paris
Hôpital Necker Enfants Malades
Nitschké, Patrick
France, Paris
Université Paris Cité
Lyonnet, Stanislas L.
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Münnich, Arnold
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Johnson, Colin A.
United Kingdom, Leeds
St James's University Hospital
Encha-Razavi, Ferechte
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Cormier-Dairé, Valeŕie
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Thauvin-Robinet, Christel
France, Dijon
Hôpital D'enfants Chu Dijon
France, Dijon
Université de Bourgogne
Vekemans, Michel J.J.
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Attié-Bitach, Tania
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Statistics
Citations: 137
Authors: 26
Affiliations: 12
Identifiers
Doi:
10.1016/j.ajhg.2012.06.017
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Cancer
Genetics And Genomics
Health System And Policy