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

Hamid Azzedine, Petra Zavadakova, Violaine Planté-Bordeneuve, Maria Vaz Pato, Nuno Pinto, Luca Bartesaghi, Jennifer Zenker, Olivier Poirot, Nathalie Bernard-Marissal, Estelle Arnaud Gouttenoire, Romain Cartoni, Alexandra Title, Giulia Venturini, Jean-Jacques Médard, Edward Makowski, Ludger Schöls, Kristl G. Claeys, Claudia Stendel, Andreas Roos, Joachim Weis, Odile Dubourg, José Leal Loureiro, Giovanni Stevanin, Gérard Said, Anthony Amato, Jay Baraban, Eric LeGuern, Jan Senderek, Carlo Rivolta, Roman Chrast
Human Molecular Genetics. 2013-06-17; 22(20): 4224-4232
DOI: 10.1093/hmg/ddt274


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1. Hum Mol Genet. 2013 Oct 15;22(20):4224-32. doi: 10.1093/hmg/ddt274. Epub 2013 Jun
17.

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

Azzedine H(1), 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 JJ, 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.

Author information:
(1)These authors contributed equally to this work.

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.

DOI: 10.1093/hmg/ddt274
PMCID: PMC3983407
PMID: 23777631 [Indexed for MEDLINE]

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