Mutations in Mediator Complex Genes CDK8 MED12 MED13 and MEDL13 Mediate Overlapping Developmental Syndromes

摘要

To identify genes that are probably causing a rare genetic disorder, medical geneticists could initially only rely on karyotyping hoping to find a de novo translocation, inversion, or deletion. Such a chromosomal rearrangement was thought to either disrupt a gene or its chromosomal context, i.e., a topologically associated domain [Poot and Haaf, 2015; Lupiáñez et al., 2016]. In this way, translocations and an inversion involving chromosomal band 7q35 produced disruptions of CNTNAP2 in patients with Gilles de la Tourette syndrome or autism [Verkerk et al., 2003; Bakkaloglu et al., 2008; Poot et al., 2010]. An apparently balanced translocation t(6;7)(q16.2;p15.3) disrupted a topologically associated domain affecting the expression of TWIST1 in a patient with Saethre Chotzen syndrome [Krebs et al., 1997]. A de novo balanced translocation t(12,17)(q24.1;q21) that interrupted the MED13L gene was found in a 7-year-old girl with postnatal microcephaly; developmental delay (DD), in particular delayed motor development and ataxia; mental retardation, with nearly absent speech; a ventricular septal defect, open foramen ovale, and coarctation of the aorta [Muncke et al., 2003]. This complex set of phenotypes suggests that MED13L is involved in regulation of development at a very early stage. This inference was supported by findings in a patient with a de novo balanced translocation t(12;19)(q24;q12) that interrupted only the MED13L gene [Utami et al., 2014]. This patient showed DD, moderate intellectual disability, very poor speech, absence seizures, cerebral atrophy, and dysmorphic facial features, including a cleft palate, glossoptosis, retrognathia, hypertelorism, flat philtrum, broad nasal bridge, bulbous nose, strabismus, and hirsutism. In addition, multiple limb contractures, camptodactyly, and foot deformities were seen. Cultured cells from this patient showed decreased mRNA and protein levels of MED13L compared to controls, which is in agreement with haploinsufficiency of this gene. While the findings from these 2 translocation carriers suggested a MED13L haploinsufficiency syndrome, the associated phenotypes appeared rather varied, and a molecular mechanism for this was not clear. Haploinsufficiency syndromes arise if the gene, of which one copy is lost, encodes a protein that is part of a signaling pathway, a protein complex, or a receptor [Veitia, 2010; Poot et al., 2011; Birchler and Veitia, 2012]. MED13L is indeed part of a protein complex, the Mediator complex (MC), which regulates transcription of mRNAs by RNA polymerase II [Conaway et al., 2005; Asadollahi et al., 2017; Harper and Taatjes, 2018].