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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.

ABSTRACT: Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous disorder. All mendelian patterns of inheritance have been described. We identified a homozygous p.A335V mutation in the MED25 gene in an extended Costa Rican family with autosomal recessively inherited Charcot-Marie-Tooth neuropathy linked to the CMT2B2 locus in chromosome 19q13.3. MED25, also known as ARC92 and ACID1, is a subunit of the human activator-recruited cofactor (ARC), a family of large transcriptional coactivator complexes related to the yeast Mediator. MED25 was identified by virtue of functional association with the activator domains of multiple cellular and viral transcriptional activators. Its exact physiological function in transcriptional regulation remains obscure. The CMT2B2-associated missense amino acid substitution p.A335V is located in a proline-rich region with high affinity for SH3 domains of the Abelson type. The mutation causes a decrease in binding specificity leading to the recognition of a broader range of SH3 domain proteins. Furthermore, Med25 is coordinately expressed with Pmp22 gene dosage and expression in transgenic mice and rats. These results suggest a potential role of this protein in the molecular etiology of CMT2B2 and suggest a potential, more general role of MED25 in gene dosage sensitive peripheral neuropathy pathogenesis.

SUBMITTER: Leal A 

PROVIDER: S-EPMC2847151 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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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.

Leal Alejandro A   Huehne Kathrin K   Bauer Finn F   Sticht Heinrich H   Berger Philipp P   Suter Ueli U   Morera Bernal B   Del Valle Gerardo G   Lupski James R JR   Ekici Arif A   Pasutto Francesca F   Endele Sabine S   Barrantes Ramiro R   Berghoff Corinna C   Berghoff Martin M   Neundörfer Bernhard B   Heuss Dieter D   Dorn Thomas T   Young Peter P   Santolin Lisa L   Uhlmann Thomas T   Meisterernst Michael M   Sereda Michael Werner MW   Sereda Michael M   Stassart Ruth Martha RM   Meyer zu Horste Gerd G   Nave Klaus-Armin KA   Reis André A   Rautenstrauss Bernd B  

Neurogenetics 20090317 4

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous disorder. All mendelian patterns of inheritance have been described. We identified a homozygous p.A335V mutation in the MED25 gene in an extended Costa Rican family with autosomal recessively inherited Charcot-Marie-Tooth neuropathy linked to the CMT2B2 locus in chromosome 19q13.3. MED25, also known as ARC92 and ACID1, is a subunit of the human activator-recruited cofactor (ARC), a family of large transcriptional coa  ...[more]