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. 2016 Apr;37(4):354-8.
doi: 10.1002/humu.22952. Epub 2016 Feb 4.

De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability

Bertrand Isidor  1   2 , Sébastien Küry  1 , Jill A Rosenfeld  3 , Thomas Besnard  1 , Sébastien Schmitt  1 , Shelagh Joss  4 , Sally J Davies  5 , Robert Roger Lebel  6 , Alex Henderson  7 , Christian P Schaaf  3 , Haley E Streff  3 , Yaping Yang  3 , Vani Jain  5 , Nodoka Chida  8 , Xenia Latypova  1 , Cédric Le Caignec  1   2 , Benjamin Cogné  1 , Sandra Mercier  1 , Marie Vincent  1 , Estelle Colin  9 , Dominique Bonneau  9 , Anne-Sophie Denommé  9 , Philippe Parent  10 , Brigitte Gilbert-Dussardier  11 , Sylvie Odent  12 , Annick Toutain  13 , Amélie Piton  14   15 , Christian Dina  16   17 , Audrey Donnart  16   17 , Pierre Lindenbaum  16   17 , Eric Charpentier  16   17 , Richard Redon  16   17 , Kenji Iemura  8 , Masanori Ikeda  8 , Kozo Tanaka  8 , Stéphane Bézieau  1
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Free article

De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability

Bertrand Isidor et al. Hum Mutat. 2016 Apr.
Free article

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 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.

Keywords: POGZ; HP1; intellectual disability; CHAMP1; kinetochores; microcephaly; microtubules.

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