Relevance to Autism

Rare variants in the MED12 gene were initially identified in ASD probands in Beyer et al., 2002, and more recently X-linked variants in MED12 have been observed in male ASD probands from the Simons Simplex Collection (Wang et al., 2020). Mutations in MED12 are associated with several syndromic forms of intellectual disability, including Opitz-Kaveggia syndrome (Risheg et al., 2007), Lujan-Fryns syndrome (Schwartz et al., 2007), and X-linked Ohdo syndrome (Vulto-van Silfhout et al., 2013). A review of phenotypes associated with MED12-related syndromes reported that behavioral abnormalities, including autistic features, were frequently observed in individuals with Lujan-Fryns syndrome (Graham and Schwartz, 2013). Polla et al., 2020 characterized a cohort of 18 females presenting with neurodevelopmental disorders and harboring de novo variants in MED12; de novo protein-truncating MED12 variants were found to associate with a severe syndromic phenotype consisting of intellectual disability, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and other variable abnormalities, whereas de novo missense variants in MED12 were associated with a less specific but homogeneous phenotype including severe intellectual disability, autism spectrum disorder or autistic features, limited speech, and other variable anomalies. Autism spectrum disorder had previously been observed in two female patients with de novo MED12 missense variants from cohorts with intellectual disability (Fieremans et al., 2016; Halvardson et al., 2016). While no genetic association has been observed between a 12-bp duplication in the MED12 gene and autism in a German population cohort (Beyer et al., 2002) and in the SCAP cohort (Michaelis et al., 2000), genetic association between this duplication and schizophrenia has been observed in a northern European population cohort (Philibert 2006).

Molecular Function

The initiation of transcription is controlled in part by a large protein assembly known as the preinitiation complex. A component of this preinitiation complex is a 1.2 MDa protein aggregate called Mediator. This Mediator component binds with a CDK8 subcomplex which contains the protein encoded by this gene, mediator complex subunit 12 (MED12), along with MED13, CDK8 kinase, and cyclin C. The CDK8 subcomplex modulates Mediator-polymerase II interactions and thereby regulates transcription initiation and reinitation rates. The MED12 protein is essential for activating CDK8 kinase. Defects in this gene cause X-linked Opitz-Kaveggia syndrome, also known as FG syndrome, and Lujan-Fryns syndrome.

External Links

References