title: Mutations in JMJD1C are involved in Rett syndrome and intellectual disability.
abstract: OBJECTIVE
  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.
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Mauricio A
authors.identifier: http://orcid.org/0000-0002-3355-7628
authors.initials: MA
authors.lastname: Sáez
authors.affiliation: Joint Biomedical Research Institute-Barcelona Supercomputing Center (IRB-BSC) Computational Biology Program, Barcelona, Catalonia, Spain.
authors.forename: Juana
authors.initials: J
authors.lastname: Fernández-Rodríguez
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Catia
authors.initials: C
authors.lastname: Moutinho
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Jose V
authors.initials: JV
authors.lastname: Sanchez-Mut
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Vidal
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Paolo
authors.identifier: http://orcid.org/0000-0002-1036-2895
authors.initials: P
authors.lastname: Petazzi
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Karolina
authors.initials: K
authors.lastname: Szczesna
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Paula
authors.identifier: http://orcid.org/0000-0001-7231-3426
authors.initials: P
authors.lastname: Lopez-Serra
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Mario
authors.identifier: http://orcid.org/0000-0002-9973-8499
authors.initials: M
authors.lastname: Lucariello
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lorden
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Raul
authors.identifier: http://orcid.org/0000-0002-8538-4087
authors.initials: R
authors.lastname: Delgado-Morales
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Olga J
authors.initials: OJ
authors.lastname: de la Caridad
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Dori
authors.initials: D
authors.lastname: Huertas
authors.affiliation: Joint Biomedical Research Institute-Barcelona Supercomputing Center (IRB-BSC) Computational Biology Program, Barcelona, Catalonia, Spain.|Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Josep L
authors.identifier: http://orcid.org/0000-0002-0566-7723
authors.initials: JL
authors.lastname: Gelpí
authors.affiliation: Joint Biomedical Research Institute-Barcelona Supercomputing Center (IRB-BSC) Computational Biology Program, Barcelona, Catalonia, Spain.|Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Catalonia, Spain.|Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
authors.forename: Modesto
authors.initials: M
authors.lastname: Orozco
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Institute for Biomedical Research (ICO-IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: López-Doriga
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic, Barcelona, Catalonia, Spain.|CIBERER (Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III), Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Milà
authors.affiliation: CIBERER (Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III), Barcelona, Spain.|Genetics Unit, University Pompeu Fabra, Barcelona, Catalonia, Spain.
authors.forename: Luís A
authors.initials: LA
authors.lastname: Perez-Jurado
authors.affiliation: CIBERER (Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III), Barcelona, Spain.|Department of Neurology, Hospital Sant Joan de Déu (HSJD), Barcelona, Catalonia, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Pineda
authors.affiliation: CIBERER (Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III), Barcelona, Spain.|Department of Neurology, Hospital Sant Joan de Déu (HSJD), Barcelona, Catalonia, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Armstrong
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Institute for Biomedical Research (ICO-IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.|Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Manel
authors.identifier: http://orcid.org/0000-0003-4490-6093
authors.initials: M
authors.lastname: Esteller
mesh_terms: D000328:Adult; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000067877:Autism Spectrum Disorder / Q000175:diagnosis / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D056726:Genetic Association Studies; D056426:Genetic Loci; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D056510:Position-Specific Scoring Matrices; D011487:Protein Conformation; D021381:Protein Transport; D015518:Rett Syndrome / Q000175:diagnosis / Q000235:genetics*
chemical_list: C520448:JMJD1C protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; D010089:Oxidoreductases, N-Demethylating