Hashimoto et al. (2011) reported a large Algerian consanguineous multiplex family in which 5 affected individuals presented with nonsyndromic intellectual disability. Two sisters were evaluated, age 39 and 41 years. The parents were healthy first cousins from Algeria. ... Hashimoto et al. (2011) reported a large Algerian consanguineous multiplex family in which 5 affected individuals presented with nonsyndromic intellectual disability. Two sisters were evaluated, age 39 and 41 years. The parents were healthy first cousins from Algeria. Pregnancy and delivery were uneventful. There were no postnatal infections, toxic exposures, or significant head trauma. The sisters were unable to read, write, or look after financial affairs, but they were independent for tasks of daily living. Mental retardation was estimated as mild to moderate. Physical exam of both patients showed normal height, weight, and head circumference. There were no dysmorphic features or malformations. Metabolic workup was unremarkable as was molecular testing which ruled out fragile X syndrome. High-resolution chromosome analysis was normal. Array CGH testing at 1-Mb resolution was normal as were bone X rays, cerebellar MRI, and EEG. Family history revealed that 2 additional sisters and 1 brother were affected with a similar condition.
Hashimoto et al. (2011) identified a G-to-A transition at nucleotide 1850 of the MED23 gene, resulting in an arg-to-gln substitution at codon 617 (R617Q; 605042.0001). Arg617 is absolutely conserved across all MED23 orthologs from Xenopus to Drosophila and ... Hashimoto et al. (2011) identified a G-to-A transition at nucleotide 1850 of the MED23 gene, resulting in an arg-to-gln substitution at codon 617 (R617Q; 605042.0001). Arg617 is absolutely conserved across all MED23 orthologs from Xenopus to Drosophila and human. The mutation does not affect MED23 expression, protein stability or architecture, or composition of the whole Mediator complex. The mutation specifically impaired the response of JUN (165160) and FOS (164810) immediate-early genes to serum mitogens by altering the interaction between enhancer-bound transcription factors (TCF4, 602272 and ELK1, 311040, respectively) and Mediator. Transcriptional dysregulation of these genes was also observed in cells derived from patients presenting with other neurologic disorders linked to mutations in other Mediator subunits or proteins interacting with the Mediator complex. These findings highlighted the crucial role of Mediator in brain development and functioning and suggested that altered immediate-early gene expression might provide a molecular signature for cognitive deficits.