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Neurogenetics ; 10(4): 275-87, 2009 10.
Article in English | MEDLINE | ID: mdl-19290556

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.


Subject(s)
Adaptor Proteins, Signal Transducing , Amino Acid Substitution , Cell Cycle Proteins , Charcot-Marie-Tooth Disease/genetics , Mediator Complex , Myelin Proteins , Nuclear Proteins , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adult , Amino Acid Sequence , Animals , Animals, Genetically Modified , Base Sequence , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Charcot-Marie-Tooth Disease/physiopathology , Costa Rica , DNA Mutational Analysis , Disease Models, Animal , Female , Gene Dosage , Genotype , Humans , Male , Mediator Complex/chemistry , Mediator Complex/genetics , Mediator Complex/metabolism , Mice , Models, Molecular , Molecular Sequence Data , Myelin Proteins/genetics , Myelin Proteins/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Pedigree , Protein Conformation , Rats
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