The term intellectual disability covers a wide range of clinical conditions, some with well-defined causes and others that remain unexplained. For example, Down syndrome results from an extra copy of chromosome 21, while Rett syndrome is often linked to mutations in the MeCP2 gene, a critical regulatory switch. Many autism spectrum disorders and other intellectual disabilities, however, lack a clear genetic explanation.
New research led by Manel Esteller, director of the Epigenetics and Cancer Biology Program (PEBC) at the Bellvitge Biomedical Research Institute (IDIBELL), ICREA researcher, and Professor of Genetics at the University of Barcelona, identifies a previously unrecognized mechanism that helps explain some of these unexplained cases. Published in the journal Genetics in Medicine, the study reports discovery of mutations in an epigenetic regulator that are implicated in certain cases of intellectual disability, autism spectrum disorders, and atypical Rett syndrome.
Esteller and colleagues analyzed the genomes of 215 patients diagnosed with intellectual disability, autism, or Rett syndrome who previously showed no genetic alterations in the genes typically associated with those disorders. Their goal was to find molecular causes that standard diagnostic screens had missed. Through comprehensive mutational and functional analysis, the team identified a new gene implicated in a subset of these conditions.
Specifically, the study highlights JMJD1C (Jumonji Domain Containing 1C), an epigenetic regulator whose normal role is to control the activity of other genes by modifying chromatin. Mutations in JMJD1C were found in a small but significant subset of patients whose conditions had no previously known genetic cause. These low-frequency but functionally impactful mutations suggest that many rare genetic disruptions across a broad set of regulatory genes may underlie unexplained intellectual disability and related neurodevelopmental disorders.
According to Esteller, “Only a small percentage of unexplained intellectual disability is due to mutations in this single gene, but identifying JMJD1C demonstrates that rare mutations in epigenetic regulators can be causal. The gene also interacts with MeCP2, indicating it may contribute to atypical forms of Rett syndrome.”
Funding: The study was supported by the European Union, Catalan and Spanish Rett syndrome associations, crowdfunding through Verkami, and the Daniel Bravo and Finestrelles Foundations, reflecting strong civil society engagement in scientific research.
Source: IDIBELL (Bellvitge Biomedical Research Institute)
Image Credit: Public domain image
Original Research: “Mutations in JMJD1C are involved in Rett syndrome and intellectual disability” by Mauricio A. Sáez et al., published in Genetics in Medicine on July 16, 2015. DOI: 10.1038/gim.2015.100
Abstract
Mutations in JMJD1C are involved in Rett syndrome and intellectual disability
Purpose:
Autism spectrum disorders and many intellectual disabilities frequently involve deficits in social interaction and communication. Rett syndrome is an example in which epilepsy, motor impairment, and other neurological symptoms co-occur. Mutations in histone demethylases and other epigenetic regulators have been linked to several neurodevelopmental syndromes. This study aimed to determine whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders.
Methods:
The researchers performed mutational screening and functional analyses of JMJD1C in a cohort of 215 individuals with autism spectrum disorders, intellectual disability, or Rett syndrome who had no previously identified genetic defect.
Results:
Seven JMJD1C variants were identified that were absent from control databases of roughly 6,000 samples and that produced amino acid substitutions altering functional biochemical groups. Among these, two de novo germline mutations in JMJD1C were discovered: one in a patient with Rett syndrome and another in a patient with intellectual disability. Functional characterization of the mutant JMJD1C protein from the Rett syndrome case revealed abnormal subcellular localization, reduced demethylation activity toward the DNA damage–response protein MDC1, and diminished interaction with MECP2. The study confirmed JMJD1C is broadly expressed across brain regions and that its depletion impairs dendritic development and neuronal function.
Conclusions:
The data indicate that rare mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability, supporting a broader role for epigenetic regulation in neurodevelopmental disorders.