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Hum Mutat. 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.

Author information

1
Service de Génétique Médicale, CHU Nantes, Nantes CEDEX 1, 44093, France.
2
INSERM, UMR-S 957, Nantes, 44035, France.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
4
Department of Clinical Genetics, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom.
5
All Wales Medical Genetic Service, University Hospital of Wales, Cardiff, United Kingdom.
6
Genetics Section, Department of Pediatrics, SUNY Upstate Medical University, Syracuse, New York.
7
Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, United Kingdom.
8
Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
9
Département de Biochimie et Génétique, CHU Angers, Angers, 49100, France et UMR INSERM 1083 - CNRS 6214.
10
Génétique Médicale, CHRU Brest, Brest, 29609, France.
11
Service de Génétique, CHU Poitiers, BP577, Poitiers 86021, France; EA 3808 Université Poitiers, France.
12
Service de Génétique Clinique, CHU Rennes, CNRS UMR6290, Université Rennes1, Rennes, France.
13
Service de Génétique, CHU Tours, Tours, 37044, France.
14
Département Médecine Translationelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de Santé et de Recherche Médicale (INSERM) U964/Centre National de Recherche Scientifique (CNRS) UMR 7104/Université de Strasbourg, Illkirch, 67404, France.
15
Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France.
16
Inserm, UMR 1087, l'institut du thorax, CHU Nantes, Nantes, France.
17
CNRS, UMR 6291, Université de Nantes, Nantes, France.

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

PMID:
26751395
DOI:
10.1002/humu.22952
[Indexed for MEDLINE]
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