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Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility  Clothilde Esteve, Ludmila.

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Presentation on theme: "Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility  Clothilde Esteve, Ludmila."— Presentation transcript:

1 Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility  Clothilde Esteve, Ludmila Francescatto, Perciliz L. Tan, Aurélie Bourchany, Cécile De Leusse, Evelyne Marinier, Arnaud Blanchard, Patrice Bourgeois, Céline Brochier-Armanet, Ange-Line Bruel, Arnauld Delarue, Yannis Duffourd, Emmanuelle Ecochard-Dugelay, Géraldine Hery, Frédéric Huet, Philippe Gauchez, Emmanuel Gonzales, Catherine Guettier-Bouttier, Mina Komuta, Caroline Lacoste, Raphaelle Maudinas, Karin Mazodier, Yves Rimet, Jean-Baptiste Rivière, Bertrand Roquelaure, Sabine Sigaudy, Xavier Stephenne, Christel Thauvin-Robinet, Julien Thevenon, Jacques Sarles, Nicolas Levy, Catherine Badens, Olivier Goulet, Jean-Pierre Hugot, Nicholas Katsanis, Laurence Faivre, Alexandre Fabre  The American Journal of Human Genetics  Volume 102, Issue 3, Pages (March 2018) DOI: /j.ajhg Copyright © 2018 American Society of Human Genetics Terms and Conditions

2 Figure 1 UNC45A Variants and Gene Structure
(A) Pedigrees of the three families with mutations in UNC45A. (B) Structural organization of UNC45A transcript (Ensembl: ENST ) and protein with known conserved protein domains and localization of amino acid residues affected by mutations identified in the three families. Exonic (in purple) regions are not drawn to scale. (C) Venn diagram showing the overlap between clinical signs of the four individuals. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2018 American Society of Human Genetics Terms and Conditions

3 Figure 2 Western Blot Detection and Quantification of UNC45A Protein in Lymphoblastoid Cells and Fibroblasts (A) Detection of UNC45A by western blot analysis in lymphoblastoid cells and fibroblasts using a monoclonal antibody. GAPDH was used as a loading control. (B and C) Quantification of UNC45A protein levels with Fiji software shows significantly lowered levels of the expression of UNC45A in all individuals’ lymphoblastoid cells (B) and fibroblasts of individual A.II.3 (C). Values are mean ratio ± SD, n = 3; Welch’s two sample t test (affected individual versus control) (∗p < 0.04). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2018 American Society of Human Genetics Terms and Conditions

4 Figure 3 Microgavage Assay to Assess Intestinal Motility
Fluorescent microspheres were gavaged and their transit was observed at 0, 3, 6, 9, and 24 hr in unc45 morphants and mutants. (A) Numbers of embryos with observed fluorescence in the four zones of the alimentary canal at four different time points. Compared to controls (left set), in which fluorescent beads peak in zone 4 at time 1 and the progressively expelled from the gut (times 2–4). Both morphants (middle set) and mutants (right set) show presence of fluorescent beads in zones 1 and 2 of the gut. (B) Representative images of the gut from controls, morphants, and mutants, demarcating the four zones and showing characteristic evidence of GFP in zones 2 and 3. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2018 American Society of Human Genetics Terms and Conditions

5 Figure 4 Histological Study of Transverse Sections of Zones 2 and 3 of 5 dpf Zebrafish Markers for F-actin (Phalloidin) and intestinal brush borders (4e8) were used and revealed defects (lack of epithelial folds in the intestinal tube) in the structure of kustr12 larvae compared to controls. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2018 American Society of Human Genetics Terms and Conditions

6 Figure 5 Assessment of Human UNC45A c.1268T>A, Resulting in a p.Val423Asp Change (V423N), on Zones 2 and 3 of Mutant unc45a Zebrafishes Mutant embryos were injected with either WT or V423N-encoding mRNA and intestinal folds were observed using brightfield microscopy. Mutants injected with WT encoding mRNA were able to restore folds in zones 2 and 3, but those injected with V423N-encoding mRNA were not restored, illustrating that V423N is pathogenic. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2018 American Society of Human Genetics Terms and Conditions

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