Mutations in JMJD1C are involved in Rett syndrome and intellectual disability

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Autism Spectrum Disorder / diagnosis
  • Autism Spectrum Disorder / genetics
  • Brain / metabolism
  • Brain / pathology
  • Conserved Sequence
  • DNA Mutational Analysis
  • Female
  • Gene Expression
  • Gene Order
  • Genetic Association Studies
  • Genetic Loci
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Jumonji Domain-Containing Histone Demethylases / chemistry
  • Jumonji Domain-Containing Histone Demethylases / genetics*
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Male
  • Middle Aged
  • Models, Molecular
  • Mutation*
  • Neurons / metabolism
  • Oxidoreductases, N-Demethylating / chemistry
  • Oxidoreductases, N-Demethylating / genetics*
  • Oxidoreductases, N-Demethylating / metabolism
  • Position-Specific Scoring Matrices
  • Protein Conformation
  • Protein Transport
  • Rett Syndrome / diagnosis
  • Rett Syndrome / genetics*


  • JMJD1C protein, human
  • Jumonji Domain-Containing Histone Demethylases
  • Oxidoreductases, N-Demethylating