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De Novo Truncating Mutations in the kinetochore-microtubules attachment gene CHAMP1 Cause Syndromic Intellectual Disability

Bertrand Isidor 1 Sébastien Küry 2 Jill A. Rosenfeld 3 Thomas Besnard 4 Sébastien Schmitt 2 Shelagh Joss 5 Sally J. Davies 6 Robert Roger Lebel 7 Alex Henderson 8 Christian P. Schaaf 3 Haley E. Streff 3 Yaping Yang 3 Vani Jain 6 Nodoka Chida 9 Xenia Latypova 2 Cédric Le Caignec 2 Benjamin Cogné 2 Sandra Mercier 2 Marie Vincent 2 Estelle Colin 10 Dominique Bonneau 11 Anne-Sophie Denommé 10 Philippe Parent 12 Brigitte Gilbert-Dussardier 13 Sylvie Odent 14 Annick Toutain 15 Amélie Piton 16 Christian Dina 17 Audrey Donnart 17 Pierre Lindenbaum 17 Eric Charpentier 17 Richard Redon 17 Kenji Iemura 9 Masanori Ikeda 9 Kozo Tanaka 9 Stéphane Bézieau 2, *
* Corresponding author
1 Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives
2 Service de Génétique
3 BCM - Baylor College of Medicine
4 Service de génétique médicale - Unité de génétique clinique [Nantes]
5 NHSGGC - NHS Greater Glasgow & Clyde [Glasgow]
6 University Hospital of Wales
7 SUNY Upstate Medical University
8 Newcastle Upon Tyne Hospitals NHS Trust
9 Tohoku University [Sendai]
10 Service de génétique [Angers]
11 Mitochondrie : Régulations et Pathologie
12 Service de Pédiatrie et de Génétique Médicale
13 Génétique Médicale
14 IGDR - Institut de Génétique et Développement de Rennes
15 Service de génétique [Tours]
16 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
17 ITX - unité de recherche de l'institut du thorax UMR1087 UMR6291
Abstract : A rare syndromic form of intellectual disability with impaired speech was recently found associated with mutations in CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), the protein product of which is directly involved in microtubule-kinetochore attachment. Through whole-exome sequencing in six unrelated non-consanguineous families having a sporadic case of intellectual disability, we identified six novel de novo truncating mutations in CHAMP1: c.1880C\textgreaterG p.(Ser627*), c.1489C\textgreaterT; p.(Arg497*), c.1876\₁877delAG; p.(Ser626Leufs*4), c.1043G\textgreaterA; p.(Trp348*), c.1002G\textgreaterA; p.(Trp334*) and c.958\₉59delCC; p.(Pro320*). Our clinical observations confirm the phenotypic homogeneity of the syndrome, which represents therefore a distinct clinical entity. Besides, our functional studies show that CHAMP1 protein variants are delocalized from chromatin and are unable to bind to two of its direct partners, POGZ and HP1. These data suggest a pathogenic mechanism of the CHAMP1-associated intellectual disability syndrome mediated by direct interacting partners of CHAMP1, several of which are involved in chromo/kinetochore-related disorders.
Keywords : HP1 Intellectual disability CHAMP1 kinetochores microcephaly Microtubules POGZ
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Submitted on : Monday, September 26, 2016 - 10:48:09 AM
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Bertrand Isidor, Sébastien Küry, Jill A. Rosenfeld, Thomas Besnard, Sébastien Schmitt, et al.. De Novo Truncating Mutations in the kinetochore-microtubules attachment gene CHAMP1 Cause Syndromic Intellectual Disability. Human Mutation, Wiley, 2016, 37 (4), pp.354-358. ⟨10.1002/humu.22952⟩. ⟨hal-01259225⟩

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