title: A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay.
abstract: Mutations in the Jumonji AT-rich interactive domain 1C (JARID1C/SMCX/KDM5C) gene, located at Xp11.22, are emerging as frequent causes of X-linked intellectual disability (XLID). KDM5C encodes for a member of an ARID protein family that harbors conserved DNA-binding motifs and acts as a histone H3 lysine 4 demethylase, suggesting a potential role in epigenetic regulation during development, cell growth and differentiation. In this study, we describe clinical and genetic findings of a Brazilian family co-segregating a novel nonsense mutation (c.2172C>A) in exon 15 of KDM5C gene with the intellectual disability phenotype. The transition resulted in replacement of the normal cysteine by a premature termination codon at position 724 of the protein (p.Cys724X), leading to reduced levels of KDM5C transcript probably due to nonsense mediated mRNA decay. The clinical phenotype of the proband, who has two affected brothers and a mild cognitively impaired mother, consisted of short stature, speech delay, hyperactivity, violent behavior and high palate, besides severe mental retardation. Our findings extend the number of KDM5C mutations implicated in XLID and highlight its promise for understanding neural function and unexplained cases of XLID.
authors.affiliation: Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil. cbs@uerj.br
authors.forename: Cíntia B
authors.initials: CB
authors.lastname: Santos-Rebouças
authors.forename: Natalia
authors.initials: N
authors.lastname: Fintelman-Rodrigues
authors.forename: Lars R
authors.initials: LR
authors.lastname: Jensen
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Kuss
authors.forename: Márcia G
authors.initials: MG
authors.lastname: Ribeiro
authors.forename: Mário
authors.initials: M
authors.lastname: Campos
authors.forename: Jussara M
authors.initials: JM
authors.lastname: Santos
authors.forename: Márcia M G
authors.initials: MM
authors.lastname: Pimentel
mesh_terms: D000293:Adolescent; D001827:Body Height / Q000235:genetics*; D001938:Brazil; D005260:Female; D056466:Histone Demethylases; D006801:Humans; D007805:Language Development Disorders / Q000235:genetics*; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D020125:Mutation, Missense; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D056466:Histone Demethylases; C086877:KDM5C protein, human; D010089:Oxidoreductases, N-Demethylating