Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models

Leal, Alejandro; Huehne, Kathrin; Bauer, F.; Sticht, Heinrich; Berger, Philipp; Suter, Ueli; Morera-Brenes, Bernal; Valle, Gerardo Del; Lupski, James R.; Ekici, Arif B.; Pasutto, Francesca; Endele, Sabine; Barrantes, Ramiro; Berghoff, Corinna; Berghoff, Martin; Neundörfer, B.; Heuss, Dieter; Dorn, Thomas; Young, Peter; Santolin, Lisa; Uhlmann, Thomas; Meisterernst, Michael; Sereda, Michael W.; Stassart, Ruth M.; Hörste, Gerd Meyer zu; Nave, Klaus‐Armin; Reis, André; Rautenstrauss, Bernd

doi:10.1007/s10048-009-0213-1

Cited by 26 publications

(23 citation statements)

References 45 publications

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“…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. Concerning MED13L, to date, three heterozygous missense mutations in patients with dTGA, one translocation disrupting MED13L between exons 1 and 2 in a patient with ID and dTGA 2 and recently, a homozygous missense mutation in two patients of a consanguineous family with non-syndromic ID were found (Table 1).…”

Section: Introductionmentioning

confidence: 90%

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

Asadollahi

Oneda

Sheth³

et al. 2013

Eur J Hum Genet

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A chromosomal balanced translocation disrupting the MED13L (Mediator complex subunit13-like) gene, encoding a subunit of the Mediator complex, was previously associated with transposition of the great arteries (TGA) and intellectual disability (ID), and led to the identification of missense mutations in three patients with isolated TGA. Recently, a homozygous missense mutation in MED13L was found in two siblings with non-syndromic ID from a consanguineous family. Here, we describe for the first time, three patients with copy number changes affecting MED13L and delineate a recognizable MED13L haploinsufficiency syndrome. Using high resolution molecular karyotyping, we identified two intragenic de novo frameshift deletions, likely resulting in haploinsufficiency, in two patients with a similar phenotype of hypotonia, moderate ID, conotruncal heart defect and facial anomalies. In both, Sanger sequencing of MED13L did not reveal any pathogenic mutation and exome sequencing in one patient showed no evidence for a non-allelic second hit. A further patient with hypotonia, learning difficulties and perimembranous VSD showed a 1 Mb de novo triplication in 12q24.2, including MED13L and MAP1LC3B2. Our findings show that MED13L haploinsufficiency in contrast to the previously observed missense mutations cause a distinct syndromic phenotype. Additionally, a MED13L copy number gain results in a milder phenotype. The clinical features suggesting a neurocristopathy may be explained by animal model studies indicating involvement of the Mediator complex subunit 13 in neural crest induction.

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Section: Introductionmentioning

confidence: 90%

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

Asadollahi

Oneda

Sheth³

et al. 2013

Eur J Hum Genet

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“…Deleterious variants in other mediator-complex genes have been described: a pericentric inversion that cause haploinsufficiency of CDK19, associated with bilateral congenital retinal folds, microcephaly, and mild intellectual disability (23); MED17 missense variants have been linked to postnatal progressive microcephaly with seizures and brain atrophy (24); MED23 variants cause autosomal recessive non-syndromic ID (25), and a homozygous MED25 variant causes autosomal recessive adult onset axonal Charcot-Marie-Tooth neuropathy (CMT2B2, MIM #605589) (26).…”

Section: Discussionmentioning

confidence: 99%

De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?

et al. 2016

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Background: Mutations in the X-linked gene MED12 cause at least three different, but closely related, entities of syndromic intellectual disability. Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies. Methods: Genotyping of 1,256 genes related with neurodevelopment was performed by next-generation sequencing in three unrelated patients and their healthy parents. Clinically relevant findings were confirmed by conventional sequencing. results: Each patient showed one de novo variant not previously reported in the literature or databases. Two different missense variants were found in the MED12 or MED13L genes and one nonsense mutation was found in the MED13L gene. conclusion: The phenotypic consequences of these mutations are closely related and/or have been previously reported in one or other gene. Additionally, MED12 and MED13L code for two closely related partners of the mediator kinase module. Consequently, we propose the concept of a common MED12/ MED13L clinical spectrum, encompassing Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L haploinsufficiency syndrome, and others.

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“…Another mutation related to neurological disorders is an R617Q mutation in MED23, which co-segregates with nonsyndromic autosomal recessive intellectual disability in families. This mutation specifically impairs the response of JUN and FOS immediate early genes to serum stimulation in patient-derived skin fibroblasts (Hashimoto et al, 2011 Charcot-Marie-Tooth disease A335V mutation (Leal et al, 2009) …”

Section: Human Diseases Related To Mediator Functionmentioning

confidence: 99%

The Mediator complex: a master coordinator of transcription and cell lineage development

2014

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Mediator is a multiprotein complex that is required for gene transcription by RNA polymerase II. Multiple subunits of the complex show specificity in relaying information from signals and transcription factors to the RNA polymerase II machinery, thus enabling control of the expression of specific genes. Recent studies have also provided novel mechanistic insights into the roles of Mediator in epigenetic regulation, transcriptional elongation, termination, mRNA processing, noncoding RNA activation and super enhancer formation. Based on these specific roles in gene regulation, Mediator has emerged as a master coordinator of development and cell lineage determination. Here, we describe the most recent advances in understanding the mechanisms of Mediator function, with an emphasis on its role during development and disease. KEY WORDS: Mediator complex, Transcription, Cell fate, Lineage development, Disease IntroductionMediator is a large, multisubunit complex that was discovered following efforts to understand how RNA polymerase II (Pol II)-mediated transcription is regulated by transcription factors in yeast (Nonet and Young, 1989;Kelleher et al., 1990;Thompson et al., 1993;Kim et al., 1994). The complex, which consists of ~30 polypeptides ( Fig. 1), shows conservation from yeast to humans and plays an indispensable role in regulating transcription. Multiple laboratories then used a variety of procedures to isolate mammalian Mediator complexes, which were named TRAP/SMCC, NAT, ARC, DRIP, Srb/MED, PC2, CRSP and mouse Mediator (Jiang et al., 1998;Sun et al., 1998; Boyer et al., 1999;Ito et al., 1999;Kingston, 1999;Näär et al., 1999;Rachez et al., 1999;Ryu et al., 1999;Malik et al., 2000). In 2004, a unified nomenclature for Mediator was established, consisting of MED1 to MED31, together with the cyclin-dependent kinase (CDK) 8-cyclin C pair and several paralogs such as MED1-like (MED1L), MED12L, MED13L and CDK19 (Bourbon et al., 2004). The Mediator complex can be divided into four distinct modules termed the head, middle, tail and CDK8 kinase module, which contains CDK8 (or its paralog CDK19), cyclin C, MED12 (or MED12L) and MED13 (or MED13L) subunits (Malik and Roeder, 2010;Taatjes, 2010). Importantly, the subunit composition of Mediator can vary and is not restricted to a single isoform. For example, immunodepletion of the Mediator complex from HeLa nuclear extracts with an anti-CDK8 antibody revealed that Mediator exists as at least two main isoforms, distinguished by the presence or absence of the CDK8 submodule (Wang et al., 2001). In addition, MED1 and MED26 are not present in all isolated isoforms (Malik and Roeder, 2010).After the initial discovery of Mediator, research mainly focused on how the Mediator complex conveys signals from transcription factors to the Pol II machinery and general transcription factors (GTFs). These studies led to the formulation of the 'bridge' model, in which Mediator connects the transcription factor and Pol II machineries and promotes formation of the pre-initiation compl...

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Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models

Cited by 26 publications

References 45 publications

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

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

De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?

The Mediator complex: a master coordinator of transcription and cell lineage development

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