PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.

Journal Article (Journal Article)

Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells.

Full Text

Duke Authors

Cited Authors

  • Azzedine, H; Zavadakova, P; Planté-Bordeneuve, V; Vaz Pato, M; Pinto, N; Bartesaghi, L; Zenker, J; Poirot, O; Bernard-Marissal, N; Arnaud Gouttenoire, E; Cartoni, R; Title, A; Venturini, G; Médard, J-J; Makowski, E; Schöls, L; Claeys, KG; Stendel, C; Roos, A; Weis, J; Dubourg, O; Leal Loureiro, J; Stevanin, G; Said, G; Amato, A; Baraban, J; LeGuern, E; Senderek, J; Rivolta, C; Chrast, R

Published Date

  • October 15, 2013

Published In

Volume / Issue

  • 22 / 20

Start / End Page

  • 4224 - 4232

PubMed ID

  • 23777631

Pubmed Central ID

  • PMC3983407

Electronic International Standard Serial Number (EISSN)

  • 1460-2083

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddt274


  • eng

Conference Location

  • England