title: De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability.
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.
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes CEDEX 1, 44093, France.|INSERM, UMR-S 957, Nantes, 44035, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes CEDEX 1, 44093, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Küry
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes CEDEX 1, 44093, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Besnard
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes CEDEX 1, 44093, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Schmitt
authors.affiliation: Department of Clinical Genetics, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom.
authors.forename: Shelagh
authors.initials: S
authors.lastname: Joss
authors.affiliation: All Wales Medical Genetic Service, University Hospital of Wales, Cardiff, United Kingdom.
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Davies
authors.affiliation: Genetics Section, Department of Pediatrics, SUNY Upstate Medical University, Syracuse, New York.
authors.forename: Robert Roger
authors.initials: RR
authors.lastname: Lebel
authors.affiliation: Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Henderson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Schaaf
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Haley E
authors.initials: HE
authors.lastname: Streff
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: All Wales Medical Genetic Service, University Hospital of Wales, Cardiff, United Kingdom.
authors.forename: Vani
authors.initials: V
authors.lastname: Jain
authors.affiliation: Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Nodoka
authors.initials: N
authors.lastname: Chida
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes CEDEX 1, 44093, France.
authors.forename: Xenia
authors.initials: X
authors.lastname: Latypova
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes CEDEX 1, 44093, France.|INSERM, UMR-S 957, Nantes, 44035, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Caignec
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes CEDEX 1, 44093, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cogné
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes CEDEX 1, 44093, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mercier
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes CEDEX 1, 44093, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vincent
authors.affiliation: Département de Biochimie et Génétique, CHU Angers, Angers, 49100, France et UMR INSERM 1083 - CNRS 6214.
authors.forename: Estelle
authors.initials: E
authors.lastname: Colin
authors.affiliation: Département de Biochimie et Génétique, CHU Angers, Angers, 49100, France et UMR INSERM 1083 - CNRS 6214.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.affiliation: Département de Biochimie et Génétique, CHU Angers, Angers, 49100, France et UMR INSERM 1083 - CNRS 6214.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Denommé
authors.affiliation: Génétique Médicale, CHRU Brest, Brest, 29609, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Parent
authors.affiliation: Service de Génétique, CHU Poitiers, BP577, Poitiers 86021, France; EA 3808 Université Poitiers, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert-Dussardier
authors.affiliation: Service de Génétique Clinique, CHU Rennes, CNRS UMR6290, Université Rennes1, Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.affiliation: Service de Génétique, CHU Tours, Tours, 37044, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.affiliation: 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.|Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Piton
authors.affiliation: Inserm, UMR 1087, l'institut du thorax, CHU Nantes, Nantes, France.|CNRS, UMR 6291, Université de Nantes, Nantes, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
authors.affiliation: Inserm, UMR 1087, l'institut du thorax, CHU Nantes, Nantes, France.|CNRS, UMR 6291, Université de Nantes, Nantes, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Donnart
authors.affiliation: Inserm, UMR 1087, l'institut du thorax, CHU Nantes, Nantes, France.|CNRS, UMR 6291, Université de Nantes, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lindenbaum
authors.affiliation: Inserm, UMR 1087, l'institut du thorax, CHU Nantes, Nantes, France.|CNRS, UMR 6291, Université de Nantes, Nantes, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Charpentier
authors.affiliation: Inserm, UMR 1087, l'institut du thorax, CHU Nantes, Nantes, France.|CNRS, UMR 6291, Université de Nantes, Nantes, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Redon
authors.affiliation: Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Iemura
authors.affiliation: Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes CEDEX 1, 44093, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bézieau
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D059472:Exome; D019066:Facies; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D017384:Sequence Deletion; D013577:Syndrome
chemical_list: C555812:CHAMP1 protein, human; D002868:Chromosomal Proteins, Non-Histone; D010750:Phosphoproteins
keywords: POGZ; HP1; intellectual disability; CHAMP1; kinetochores; microcephaly; microtubules