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De Novo Mutations in Genes of Mediator Complex Causing Syndromic Intellectual Disability: Mediatorpathy Or Transcriptomopathy?

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De Novo Mutations in Genes of Mediator Complex Causing Syndromic Intellectual Disability: Mediatorpathy Or Transcriptomopathy? nature publishing group Clinical Investigation Articles De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy? Alfonso Caro-Llopis1, Monica Rosello1, Carmen Orellana1, Silvestre Oltra1, Sandra Monfort1, Sonia Mayo1 and Francisco Martinez1 BACKGROUND: Mutations in the X-linked gene MED12 cause middle, and tail modules and all together form the core Mediator at least three different, but closely related, entities of syndromic Complex that interacts directly with RNA polymerase II and intellectual disability. Recently, a new syndrome caused by both general and gene-specific transcription factors (5,6), and MED13L deleterious variants has been described, which shows a fourth “kinase” module that reversibly associates with the similar clinical manifestations including intellectual disability, core complex which is composed by MED12, MED13, CDK8, hypotonia, and other congenital anomalies. and CCNC or their paralogs MED12L, MED13L, and CDK19 METHODS: Genotyping of 1,256 genes related with neuro- (7,8). This module was primarily thought to be involved in development was performed by next-generation sequencing transcriptional repression by blocking the binding of the core in three unrelated patients and their healthy parents. Clinically Mediator Complex to RNA polymerase II because Mediators relevant findings were confirmed by conventional sequencing. containing this module are less active than in its absence (4,9). RESULTS: Each patient showed one de novo variant not previ- However, there are growing evidences that the kinase module ously reported in the literature or databases. Two different mis- is also involved in transcriptional activation (10). sense variants were found in the MED12 or MED13L genes and MED12 gene variants cause at least three different syn- one nonsense mutation was found in the MED13L gene. dromes: Opitz-Kaveggia (FG) (MIM #305450), Lujan-Fryns CONCLUSION: The phenotypic consequences of these muta- (MIM #309520), and Ohdo (Maat-Kievit-Brunner type, or tions are closely related and/or have been previously reported OSMKB) (MIM #300895). They all have similar clinical mani- in one or other gene. Additionally, MED12 and MED13L code festations with multiple congenital anomalies, macrocephaly, for two closely related partners of the mediator kinase module. hypotonia, and moderate to severe intellectual disability (11). Consequently, we propose the concept of a common MED12/ MED13L mutations were initially described in patients with MED13L clinical spectrum, encompassing Opitz-Kaveggia syn- congenital heart defect (transposition of the great arteries). drome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L hap- However, according to recent studies, the cardiac phenotype loinsufficiency syndrome, and others. is an unclear feature associated with variants of the MED13L gene (12–16). Recently, Adegbola and colleagues have described the clinical features caused by MED13L deleterious egulation of gene expression in eukaryotes is an extremely variants. All individuals had intellectual disability and share Rcomplex process that is controlled by several mechanisms characteristic facial features, delayed speech and language at multiple stages (1). Alterations of transcriptional regulation development, hypotonia, poor coordination, and behavioral are involved in the pathogenesis of many human diseases and problems. None of the patients had a complex congenital most of the affected signaling pathways finally target the core heart defect (17). transcriptional machinery (2). Here, we report on one patient with a de novo MED12 muta- MED12 (Mediator Complex Subunit 12) and MED13L tion and two patients with de novo MED13L mutations, not (Mediator Complex Subunit 13 like) encode two subunits of previously described. The clinical features in these patients and the macromolecular complex known as “Mediator transcrip- in the ones previously reported indicate that mutations in both tion co-activator complex”. The mediator interacts with gen- genes result in similar phenotypes. eral transcription factors and RNA polymerase II to regulate transcription. It is the essential coactivator acting as a bridge RESULTS molecule between transcription factors bound at upstream All three patients had a normal karyotype and were negative DNA regulatory elements and the transcriptional machinery. for fragile-X mutation. For the three patients, whole genome This complex consists of four distinct modules (3,4): the head, dosage analysis was performed by 44K oligonucleotide array 1Genetics Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain. Correspondence: Francisco Martinez ([email protected]) Received 29 February 2016; accepted 13 June 2016; advance online publication 14 September 2016. doi:10.1038/pr.2016.162 Copyright © 2016 International Pediatric Research Foundation, Inc. Volume 80 | Number 6 | December 2016 Pediatric ResearcH 809 Articles Caro-Llopis et al. CGH (G4426B Agilent Technologies, Palo Alto, CA). No other mutations in the MEDs genes (see Table 2). As it can be pathogenic variants were detected. observed, there is a wide clinical spectrum among the patients By applying next-generation sequencing, we identified two carrying a mutation in MED12 or among those with mutation novel heterozygous potentially relevant missense variants in MED13L. However, the range of clinical manifestations that and one nonsense mutation in the MED12 or MED13L genes can be present when MED12 or MED13L are mutated is strik- (Figure 1). Patient 1 showed the de novo mutation c.887G>A in ingly similar. For instance, it is worthy to note that all the fea- the MED12 gene (NM_005120.2), which causes the aminoacid tures shared by patients 2 and 3, both of them with mutation in change arginine to glutamine at position 296 of the protein. the MED13L gene (hypotonia, low-set ears, strabismus, hyper- Patient 2 carries a de novo variant c.5695G>A in the MED13L telorism, epicantal folds, down-slanting palpebral fissures and gene (NM_015335.4), which is predicted to substitute the depressed nasal bridge, in addition to intellectual disability) glycine at position 1899 by arginine. Both substitutions affect are equally reported not only among patients with MED13L highly conserved aminoacids. In silico predictions of functional mutations, but also in the Opitz-Kaveggia or Lujan-Fryns syn- relevance suggested a pathogenic effect for both variants (see dromes (see Table 2). Table 1) which, together with the fact of occurring de novo, are Our results support the findings reported by Adegbola et al. highly suggestive of their pathogenic effect. Patient 3 showed (17) regarding the absence of congenital heart disease the nonsense mutation c.2524C>T (NM_015335.4), which generates a premature stop codon at exon 14 of the MED13L Table 1. De novo mutations detected in MED12 and MED13L gene. These mutations were not detected in available databases, Patient 1 Patient 2 Patient 3 including the 1000 Genomes database (EMBL-EBI, Hinxton, Cambridge, UK), dbSNP142, the Exome Variant Server (EVS) Position chrX:70341452G>A chr12:116413012C>T chr12:116440853G>A (Washington, MO), and the Exome Aggregation Consortium Gene MED12 MED13L MED13L (ExAC) (Cambridge, MA). All variants were submitted to the Coding c.887G>A c.5695G>A c.2524C>T DECIPHER database (Hinxton, Cambridge, UK). Transcript NM_005120.2 NM_015335.4 NM_015335.4 Protein p.Arg296Gln p.Gly1899Arg p.Arg842Ter DISCUSSION Exon 7 25 14 In this study, we report one patient with MED12 and two patients with MED13L de novo mutations. All of them dis- SIFT 0.01 0.0 - play common characteristic facial features, have intellectual PPH2 1.0 1.0 - disability, speech impairment, motor developmental delay MA 2.74 2.815 - with muscular hypo- or hypertonia and behavioral difficul- FATHMM 1.29 -1.87 - ties. Furthermore, most of the additional clinical features CONDEL 0.527 0.649 - of these patients were previously reported in association to a Patient 1 Arg296Gln Arg961Trp (20) Arg1148His Ala1383Thr (20) His1729Asn (19) Ser1967Glnfsx84 (20) Gly958Glu (20) (19) Asn1007Ser (18) Ser1165Pro (19) b Patient 2 Patient 3 Gly1899Arg Arg842Ter Gly2040Asnfs*32 (14) Lys1474Ter (16) Pro1255Profs*3 (16) Asp860Gly (15) Ser570Phefs*27 (17) c.480-1 G>T (17) Ser203Serfs*32 (16) Gln1984Alafs*31 (17) Arg1416His (17) (17) (17) (17) (17) (17) (17) (17) (17) (17) (17) (13) Figure 1. Distribution of point mutations along MED12 and MED13L genes. Schematic presentation of the MED12 (a) and MED13L (b) genes (intronic regions are not drawn to scale). The mutations identified in the patients reported here are represented by a cross, and previously published mutations are indicated by a rhomb (if mutations are single nucleotide ­variant), dotted line (if mutations are duplications) or dashed line (if mutations are deletions). 810 Pediatric ResearcH Volume 80 | Number 6 | December 2016 Copyright © 2016 International Pediatric Research Foundation, Inc. Copyright © 2016 International Pediatric Research Foundation, Inc. Foundation, Research ©2016InternationalCopyright Pediatric Table 2. Clinical features of patients with mutations in MED12 and MED13L genes MED13L MED12 MED12 MED12 Patient 1 Patient 2 Patient 3 Adegbola et al. MED13L van Schwartz et al. MED12 (OHDO (OPITZ-KAVEGGIA (LUJAN-FRYNS MED12 MED13L MED13L (eight patients) Haelst et al. (seven patients) syndrome)a syndrome)a syndrome)a Arg296Gln Gly1899Arg Arg842Ter (17) (4 patients) (13) (18) Growth Weight Low Low Low Low (28.6%) paramers Height Short
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