MED23 Mutation Links Intellectual Disability to Dysregulation of Immediate Early Gene Expression

Abstract

MED23 is a subunit of the Mediator complex, a key regulator of protein-coding gene expression. Here, we report a missense mutation (p. R617Q) in MED23 that cosegregates with nonsyndromic autosomal recessive intellectual disability. This mutation specifically impaired the response of JUN and FOS immediate early genes (IEGs) to serum mitogens by altering the interaction between enhancer-bound transcription factors (TCF4 and ELK1, respectively) and Mediator. Transcriptional dysregulation of these genes was also observed in cells derived from patients presenting with other neurological disorders linked to mutations in other Mediator subunits or proteins interacting with MED. These findings highlight the crucial role of Mediator in brain development and functioning and suggest that altered IEG expression might be a common molecular hallmark of cognitive deficit.

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

“…309520), 5 X-linked disorders characterized by ID, hypotonia and minor anomalies such as macrocephaly or high forehead and rarely congenital heart defects. For the other members of the Mediator complex, the following disease associations have been reported so far: an 800 kb heterozygous deletion including MED13 in a patient with ID, cataract and hearing loss, 6 association of infantile cerebral and cerebellar atrophy with a homozygous missense mutation in MED17, 7 co-segregation of a missense mutation in MED23 with nonsyndromic autosomal recessive ID 8 and a homozygous missense mutation of MED25 in a family with Charcot-Marie-Tooth neuropathy. 9 These findings highlight the importance of the Mediator complex in embryonic development and in particular of the nervous system.…”

Redefining the MED13L syndrome

“…4 Although in these cases, the individual effect of increased MED13L dosage cannot be determined because of the involvement of several genes, it further underlines a possible gene dosage effect. MED13L is only one component of the mediator complex linked to human disease: (i) MED12 gene variants cause Lujan-Fryns syndrome (MIM #309520), 25 Ohdo syndrome (MIM #300895), 26 Opitz-Kaveggia syndrome (MIM #305450), 27 and profound ID that in contrast to the aforementioned syndromes resulted in affected female carriers and truncation of the MED12 protein, 28 (ii) a recurrent homozygous MED17 missense variant has been linked to postnatal progressive microcephaly with seizures and brain atrophy (MIM #613668), 29 (iii) a homozygous MED23 variant causes autosomal recessive nonsyndromic ID (MIM #614249), 30 (iv) a homozygous MED25 variant causes autosomal recessive adult onset axonal Charcot-Marie-Tooth neuropathy (CMT2B2, MIM #605589) 31 and (v) a truncation of CDK19 caused by a chromosome inversion is associated with bilateral congenital retinal folds, microcephaly, and mild ID (MIM #614720). 32 We observe that the MED13L phenotype displays similarities to OpitzKaveggia syndrome, along with key differences (see Table 3).…”

Mediator links transcription and DNA repair by facilitating Rad2/XPG recruitment

“…Mutations that affect Mediator subunits lead to a number of human pathologies Schwartz et al 2007). Recently, mutations in the Med17 Mediator subunit have been associated with infantile cerebral atrophy (Kaufmann et al 2010), and a mutation in the Med23 subunit cosegregated with intellectual disability (Hashimoto et al 2011). Since oncogenesis results from gene disregulation, it is not unexpected that Mediator is involved in several cancers (Zhang et al 2005;Vijayvargia et al 2007;Firestein et al 2008;Gade et al 2009;Li et al 2010;Kuuselo et al 2011).…”