Premium
De Novo Truncating Mutations in the Kinetochore‐Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability
Author(s) -
Isidor Bertrand,
Küry Sébastien,
Rosenfeld Jill A.,
Besnard Thomas,
Schmitt Sébastien,
Joss Shelagh,
Davies Sally J,
Roger Lebel Robert,
Henderson Alex,
Schaaf Christian P.,
Streff Haley E.,
Yang Yaping,
Jain Vani,
Chida Nodoka,
Latypova Xenia,
Caignec Cédric Le,
Cogné Benjamin,
Mercier Sandra,
Vincent Marie,
Colin Estelle,
Bonneau Dominique,
Denommé AnneSophie,
Parent Philippe,
GilbertDussardier Brigitte,
Odent Sylvie,
Toutain Annick,
Piton Amélie,
Dina Christian,
Donnart Audrey,
Lindenbaum Pierre,
Charpentier Eric,
Redon Richard,
Iemura Kenji,
Ikeda Masanori,
Tanaka Kozo,
Bézieau Stéphane
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22952
Subject(s) - biology , genetics , intellectual disability , chromatin , exome sequencing , gene , kinetochore , phenotype , exome , chromosome
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 nonconsanguineous families having a sporadic case of intellectual disability, we identified six novel de novo truncating mutations in CHAMP1 : c.1880C>G p.(Ser627*), c.1489C>T; p.(Arg497*), c.1876_1877delAG; p.(Ser626Leufs*4), c.1043G>A; p.(Trp348*), c.1002G>A; 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.