Mutations in JMJD1C are involved in Rett syndrome and intellectual disability

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

C57BL/6J and C57BL/6N substrains differentially influence phenotype severity in the Scn1a+/− mouse model of Dravet syndrome

“…Jmjd1c encodes a putative histone demethylase. Sáez et al reported heterozygous de novo variants in JMJD1C in 2 unrelated individuals with Rett syndrome and showed reduced dendritic complexity with small interfering RNA knockdown in mouse hippocampal neurons. C57BL/6J codes for a leucine at position 1715, whereas C57BL/6NJ and other strains have a proline in this position (rs13480628), although the effect on protein function is predicted to be benign .…”

De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

“…In addition, germline variants in the H3K9 demethylase JMJD1C (MIM: 604503), which is a gene that shows large regions of homology with KDM3B, are found in individuals with intracranial germ cell tumors and with NDDs. 26,27 Rare de novo KDM3B variants (c.4216C>T [p.Arg1406Trp] 28 and c.2624del [p.Leu875Argfs*8]) 4 have been reported in two individuals with schizophrenia and ID, respectively. However, the associated phenotypes have not been fully reported, nor was the causality of these variants confirmed.…”

Chromosomal microarray and whole‐exome sequence analysis in Taiwanese patients with autism spectrum disorder

“…The p.F2115C mutation is in the JmjC domain, a domain family that is part of the cupin metalloenzyme superfamily. Mutations in this gene are associated with Rett syndrome and intellectual disability (Saez et al, ). TCF12 encodes a member of the basic helix‐loop‐helix E‐protein family that recognizes the consensus‐binding site (E‐box) CANNTG.…”