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.
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.
Leal
Alejandro
A
Institute of Human Genetics, Friedrich-Alexander University, Schwabachanlage 10, 91054, Erlangen, Germany.
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
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
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