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

被引：54

作者：

Leal, Alejandro ^{[2
,3
,4
,5
]}

Huehne, Kathrin ^{[2
]}

Bauer, Finn ^{[6
]}

Sticht, Heinrich ^{[6
]}

Berger, Philipp ^{[7
]}

Suter, Ueli ^{[7
]}

Morera, Bernal ^{[8
]}

Del Valle, Gerardo ^{[9
]}

Lupski, James R. ^{[10
]}

Ekici, Arif ^{[2
]}

Pasutto, Francesca ^{[2
]}

Endele, Sabine ^{[2
]}

Barrantes, Ramiro ^{[3
]}

Berghoff, Corinna ^{[11
]}

Berghoff, Martin ^{[12
]}

Neundoerfer, Bernhard ^{[13
]}

Heuss, Dieter ^{[13
]}

Dorn, Thomas ^{[14
]}

Young, Peter ^{[11
]}

Santolin, Lisa ^{[15
]}

Uhlmann, Thomas ^{[15
]}

Meisterernst, Michael ^{[15
]}

Sereda, Michael ^{[16
]}

zu Horste, Gerd Meyer ^{[16
]}

Nave, Klaus-Armin ^{[16
]}

Reis, Andre ^{[2
]}

Rautenstrauss, Bernd ^{[1
,2
]}

机构：

[1] Med Genet Zentrum, D-80335 Munich, Germany

[2] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany

[3] Univ Costa Rica, Sch Biol, San Jose, Costa Rica

[4] Univ Costa Rica, Inst Hlth Res, INISA, San Jose, Costa Rica

[5] Univ Costa Rica, Neurosci Res Program, San Jose, Costa Rica

[6] Univ Erlangen Nurnberg, Inst Biochem, Emil Fischer Zentrum, D-91054 Erlangen, Germany

[7] ETH, Swiss Fed Inst Technol, HPM II E39, ETH Honggerberg,Inst Cell Biol, CH-8093 Zurich, Switzerland

[8] Univ Nacl, Sch Biol Sci, Heredia, Costa Rica

[9] Neurolab, Lab Neurol, San Jose, Costa Rica

[10] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[11] Univ Munster, Dept Neurol, D-48129 Munster, Germany

[12] Klinikum Justus Liebig Univ, D-35385 Giessen, Germany

[13] Univ Erlangen Nurnberg, Dept Neurol, D-91054 Erlangen, Germany

[14] Schweizer Epilepsie Zentrum, CH-8008 Zurich, Switzerland

[15] GSF Natl Res Ctr Environm & Hlth, Inst Immunol, D-81375 Munich, Germany

[16] Max Planck Inst Expt Med, Dept Neurogenet, D-37075 Gottingen, Germany

来源：

NEUROGENETICS | 2009年 / 10卷 / 04期

基金：

瑞士国家科学基金会;

关键词：

CMT; HMSN; MED25; PMP22; CMT2B2; ACID1; ARC92; MARIE-TOOTH-DISEASE; PERIPHERAL NEUROPATHIES; TYROSINE KINASE; AXONAL FORM; GENE; MUTATIONS; PROTEIN; MAPS; DOMAIN; MECHANISMS;

D O I：

10.1007/s10048-009-0183-3

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：275 / 287

页数：13

共 56 条

[1] HYPERMYELINATION AND DEMYELINATING PERIPHERAL NEUROPATHY IN PMP22-DEFICIENT MICE [J].