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Genet Med. 2016 Apr;18(4):378-85. doi: 10.1038/gim.2015.100. Epub 2015 Jul 16.

Mutations in JMJD1C are involved in Rett syndrome and intellectual disability.

Author information

1
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
2
Joint Biomedical Research Institute-Barcelona Supercomputing Center (IRB-BSC) Computational Biology Program, Barcelona, Catalonia, Spain.
3
Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Catalonia, Spain.
4
Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
5
Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Institute for Biomedical Research (ICO-IDIBELL), Barcelona, Catalonia, Spain.
6
Biochemistry and Molecular Genetics Department, Hospital Clínic, Barcelona, Catalonia, Spain.
7
CIBERER (Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III), Barcelona, Spain.
8
Genetics Unit, University Pompeu Fabra, Barcelona, Catalonia, Spain.
9
Department of Neurology, Hospital Sant Joan de Déu (HSJD), Barcelona, Catalonia, Spain.
10
Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain.

Abstract

PURPOSE:

Autism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which epilepsy, motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are known to occur in several of these syndromes. Herein, we aimed to identify whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders.

METHODS:

We performed the mutational and functional analysis of JMJD1C in 215 cases of autism spectrum disorders, intellectual disability, and Rett syndrome without a known genetic defect.

RESULTS:

We found seven JMJD1C variants that were not present in any control sample (~ 6,000) and caused an amino acid change involving a different functional group. From these, two de novo JMJD1C germline mutations were identified in a case of Rett syndrome and in a patient with intellectual disability. The functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity.

CONCLUSIONS:

Our findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability.Genet Med 18 1, 378-385.

PMID:
26181491
PMCID:
PMC4823641
DOI:
10.1038/gim.2015.100
[Indexed for MEDLINE]
Free PMC Article

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