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CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

ABSTRACT: Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

SUBMITTER: Snijders Blok L

PROVIDER: S-EPMC6218476 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

Snijders Blok Lot L Rousseau Justine J Twist Joanna J Ehresmann Sophie S Takaku Motoki M Venselaar Hanka H Rodan Lance H LH Nowak Catherine B CB Douglas Jessica J Swoboda Kathryn J KJ Steeves Marcie A MA Sahai Inderneel I Stumpel Connie T R M CTRM Stegmann Alexander P A APA Wheeler Patricia P Willing Marcia M Fiala Elise E Kochhar Aaina A Gibson William T WT Cohen Ana S A ASA Agbahovbe Ruky R Innes A Micheil AM Au P Y Billie PYB Rankin Julia J Anderson Ilse J IJ Skinner Steven A SA Louie Raymond J RJ Warren Hannah E HE Afenjar Alexandra A Keren Boris B Nava Caroline C Buratti Julien J Isapof Arnaud A Rodriguez Diana D Lewandowski Raymond R Propst Jennifer J van Essen Ton T Choi Murim M Lee Sangmoon S Chae Jong H JH Price Susan S Schnur Rhonda E RE Douglas Ganka G Wentzensen Ingrid M IM Zweier Christiane C Reis André A Reis André A Bialer Martin G MG Moore Christine C Koopmans Marije M Brilstra Eva H EH Monroe Glen R GR van Gassen Koen L I KLI van Binsbergen Ellen E Newbury-Ecob Ruth R Bownass Lucy L Bader Ingrid I Mayr Johannes A JA Wortmann Saskia B SB Jakielski Kathy J KJ Strand Edythe A EA Kloth Katja K Bierhals Tatjana T Roberts John D JD Petrovich Robert M RM Machida Shinichi S Kurumizaka Hitoshi H Lelieveld Stefan S Pfundt Rolph R Jansen Sandra S Deriziotis Pelagia P Faivre Laurence L Thevenon Julien J Assoum Mirna M Shriberg Lawrence L Kleefstra Tjitske T Brunner Han G HG Wade Paul A PA Fisher Simon E SE Campeau Philippe M PM

Nature communications 20181105 1

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 ...[more]

PMID: 30397230

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Project description:Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

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CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

Publications

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

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