Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect

Abstract

Purpose: Mediator is a multiprotein complex that allows the transfer of genetic information from DNA binding proteins to the RNA polymerase II during transcription initiation. MED12L is a subunit of the kinase module, which is one of the four subcomplexes of the mediator complex. Other subunits of the kinase module have been already implicated in intellectual disability, namely MED12, MED13L, MED13, and CDK19.

Methods: We describe an international cohort of seven affected individuals harboring variants involving MED12L identified by array CGH, exome or genome sequencing.

Results: All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment. Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features. Three individuals had a MED12L deletion or duplication. The other four individuals harbored single-nucleotide variants (one nonsense, one frameshift, and two splicing variants). Functional analysis confirmed a moderate and significant alteration of RNA synthesis in two individuals.

Conclusion: Overall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect. Our findings confirm that the integrity of this kinase module is a critical factor for neurological development.

Keywords: MED12L; corpus callosum; intellectual disability; mediator complex; transcriptional defect.

Figure 1:. Photographs and brain MRI of individuals with variants in MED12L.

A, Individual 1: unilateral ptosis with iris coloboma, hypertelorism, sparse eyebrows, downslanted palpebral fissures, bulbous nasal tip. B, Individual 2: prominent nasal bridge, short philtrum, everted lower lip, small mouth. C, Individual 5: deep-set eyes, bulbous nasal tip, thin upper lip, triangular face. Brain MRI shows mildly hypoplastic corpus callosum, which is foreshortened with a small splenium.

Figure 2:

A. Genomic position of MED12L variants identified in our series. Upper panel represents single nucleotide variants. Lower panel represents copy-number variants. B. Localization of predicted domains of MED12L protein.

Figure 3:. Recovery of RNA synthesis (RRS) following UV irradiation.

Fibroblasts of individuals 1 (∆) and 2 (○) show a moderately decreased level of RRS as compared to the normal control cell line (♦), similar to a MED12 mutated cell line (●). A MED13L mutated cell line (▯) shows a more severely decreased RRS level, closer to the typical severely decreased level of RRS in a CSA defective cell line (■). Error bars represent standard errors of the mean.