TCTN3 Mutations Cause Mohr-Majewski Syndrome

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TCTN3 Mutations Cause Mohr-Majewski Syndrome Sophie Thomas, Marine Legendre, Sophie Saunier, Bettina Bessières, Caroline Alby, Maryse Bonnière, Annick Toutain, Laurence Loeuillet, Katarzyna Szymanska, Frédérique Jossic, Dominique Gaillard, Mohamed Tahar Yacoubi, Soumaya Mougou-Zerelli, Albert David, Marie-Anne Barthez, Yves Ville, Christine Bole-Feysot, Patrick Nitschke, Stanislas Lyonnet, Arnold Munnich, Colin A. Johnson, Férechté Encha-Razavi, Valérie Cormier-Daire, Christel Thauvin-Robinet, Michel Vekemans, Tania Attié-Bitach The American Journal of Human Genetics Volume 91, Issue 2, Pages 372-378 (August 2012) DOI: 10.1016/j.ajhg.2012.06.017 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Phenotype of Fetuses and TCTN3 Mutation Identification (A–D) Pictures of fetus 10047, showing lobulated tongue (A), postaxial polydactyly of the hand (B), bowing of long bones, a trident appearance of acetabular bones but no short ribs (C), and severe tibia hypoplasia (D). (E–H) Pictures of fetus 11385, showing lingual hamartoma (E), postaxial polydactyly of the hand (F), moderate bowing of long bones (G), and slightly thickened tibia bones (H). (I) After homozygosity mapping with Affymetrix 250 SNP microarrays, a ciliary gene exome sequencing and filtering of the data identified a unique nonsense mutation in one of the targeted homozygous regions. The American Journal of Human Genetics 2012 91, 372-378DOI: (10.1016/j.ajhg.2012.06.017) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Analysis of Ciliogenesis and SHH Pathway in TCTN3 Mutants (A) Analysis of the primary cilia in kidneys of two affected fetuses aged 14.5 and 19 gestation weeks (gw), respectively (cases 860 and 10047), compared to a matched control, costained with acetylated α tubulin (red; Sigma) and pericentrin (green; AbCam). Confocal images were taken with a Leica SP5 confocal microscope. (B) TCTN3-mutated patient fibroblasts failed to upregulate GLI1 and PTCH1 after stimulation with Smoothened Agonist (SAG) for 18 hr, as compared to controls. Primers used for quantitative RT-PCR are listed in Table S5. Values were normalized to GAPDH and presented as relative expression levels ± SEM. ∗∗p < 0.05, ∗∗∗p < 0.001 (Student’s two-tailed t test). (C) Immunoblot analysis with the use of a GLI3 antibody (Santa Cruz Biotechnology) showed that TCTN3 processing of GLI3 into the repressor form, GLI3R, is increased in TCTN3-mutated fibroblasts as compared to controls. A graphical evaluation of the GLI3-FL:GLI3-R ratio using actin as a loading control and ImageJ software for densitometry is presented. The American Journal of Human Genetics 2012 91, 372-378DOI: (10.1016/j.ajhg.2012.06.017) Copyright © 2012 The American Society of Human Genetics Terms and Conditions