CMT2B2: Identification of the variant Ala335Val of MED25 as responsible; molecul

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Neurogenetics. 2009 Mar 17.

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 A, Huehne K, Bauer F, Sticht H, Berger P, Suter U, Morera B, Del Valle G,

Lupski JR, Ekici A, Pasutto F, Endele S, Barrantes R, Berghoff C, Berghoff M,

Neundörfer B, Heuss D, Dorn T, Young P, Santolin L, Uhlmann T, Meisterernst M,

Sereda M, Zu Horste GM, Nave KA, Reis A, Rautenstrauss B.

Institute of Human Genetics, Friedrich- University, Schwabachanlage 10,

91054, Erlangen, Germany.

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.