Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia

Abstract

Background Mutations in the JARID1C (Jumonji AT-rich interactive domain 1C) gene were recently associated with X-linked mental retardation (XLMR). Mutations in this gene are reported to be one of the relatively more common causes of XLMR with a frequency of approximately 3% in males with proven or probable XLMR. The JARID1C protein functions as a histone 3 lysine 4 (H3K4) demethylase and is involved in the demethylation of H3K4me3 and H3K4me2. Methods Mutation analysis of the JARID1C gene was conducted in the following cohorts: probands from 23 XLMR families linked to Xp11.2, 92 males with mental retardation and short stature, and 172 probands from small XLMR families with no linkage information. Results Four novel mutations consisting of two missense mutations, p.A77T and p.V504M, and two frame shift mutations, p.E468fsX2 and p.R1481fsX9, were identified in males with mental retardation. Two of the mutations, p.V504M and p.E468fsX2, are located in the JmjC domain of the JARID1C gene where no previous mutations have been reported. Additional studies showed that the missense mutation, p.V504M, was a de novo event on the grandpaternal X chromosome of the family. Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%). The degree of mental retardation consisted of mild (25%), moderate (12%) and severe (63%). Conclusion Based on the clinical observations, male patients with mental retardation, short stature and hyperreflexia should be considered candidates for mutations in the JARID1C gene.

Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype–phenotype correlation

“…5 Together with another missense change recently published, 6 these are the only two mutations predicted to affect the Jmjc domain function directly. Both mutations have been found in families with relatively mild intellectual disability.…”

“…Currently, there are 20 mutations, including the two reported in this study, in 52 affected males ( Figure 5, Table 2). 2,[6][7][8][9] Some carrier females, with generally mild intellectual disability, have also been reported. These include three carrier females from the K8545 family of Abidi et al, 6 one carrier female from the family N063 of Jensen et al, 2 one from family A015 of Tzschach et al, 9 and one from Family 1 and two from Family 2 (see above) reported here.…”

“…The most common features observed in affected individuals reported to date are hyperreflexia, short stature, aggressive behavior and seizures. 6 Microcephaly has been reported infrequently. 6,7,9 The JARID1C protein was previously identified with REST at the RE1 elements of several target genes.…”

“…6 Microcephaly has been reported infrequently. 6,7,9 The JARID1C protein was previously identified with REST at the RE1 elements of several target genes. 5 Some of them are neuronal genes associated with epilepsy and psychiatric disorders, such as SCN2A, CACNAH1 and SLC6A3.…”

“…4,5 Mutations in the JARID1C gene have been reported in patients with X-linked mental retardation (XLMR). 2,[6][7][8][9] Eighteen mutations in JARID1C have been reported to date and are spread throughout the gene. Affected individuals with JARID1C mutations show a mild-tosevere range of intellectual disability.…”