title: 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.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander University, Schwabachanlage 10, 91054, Erlangen, Germany.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Leal
authors.forename: Kathrin
authors.initials: K
authors.lastname: Huehne
authors.forename: Finn
authors.initials: F
authors.lastname: Bauer
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.forename: Philipp
authors.initials: P
authors.lastname: Berger
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.forename: Bernal
authors.initials: B
authors.lastname: Morera
authors.forename: Gerardo
authors.initials: G
authors.lastname: Del Valle
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Arif
authors.initials: A
authors.lastname: Ekici
authors.forename: Francesca
authors.initials: F
authors.lastname: Pasutto
authors.forename: Sabine
authors.initials: S
authors.lastname: Endele
authors.forename: Ramiro
authors.initials: R
authors.lastname: Barrantes
authors.forename: Corinna
authors.initials: C
authors.lastname: Berghoff
authors.forename: Martin
authors.initials: M
authors.lastname: Berghoff
authors.forename: Bernhard
authors.initials: B
authors.lastname: Neundörfer
authors.forename: Dieter
authors.initials: D
authors.lastname: Heuss
authors.forename: Thomas
authors.initials: T
authors.lastname: Dorn
authors.forename: Peter
authors.initials: P
authors.lastname: Young
authors.forename: Lisa
authors.initials: L
authors.lastname: Santolin
authors.forename: Thomas
authors.initials: T
authors.lastname: Uhlmann
authors.forename: Michael
authors.initials: M
authors.lastname: Meisterernst
authors.forename: Michael Werner
authors.initials: MW
authors.lastname: Sereda
authors.forename: Michael
authors.initials: M
authors.lastname: Sereda
authors.forename: Ruth Martha
authors.initials: RM
authors.lastname: Stassart
authors.forename: Gerd
authors.initials: G
authors.lastname: Meyer zu Horste
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Bernd
authors.initials: B
authors.lastname: Rautenstrauss
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D003364:Costa Rica; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D011487:Protein Conformation; D051381:Rats
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C470309:MAD2L1BP protein, human; C483045:MED25 protein, human; D056892:Mediator Complex; D009185:Myelin Proteins; D009687:Nuclear Proteins; C073687:PMP22 protein, human