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 Schö ls, Kristl G. Claeys, Claudia Stendel, Andreas Roos, Joachim WeisOdile Dubourg, José Leal Loureiro, Giovanni Stevanin, Gérard Said, Anthony Amato, Jay Baraban, Eric LeGuern, Jan Senderek, Carlo Rivolta, Roman Chrast

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Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterizedbyprogressive distalmuscleweaknessandatrophy, foot deformitiesanddistal sensory loss. Following the analysis of two consanguineous families affected by amedium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with acombined 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.

Original languageEnglish
Article numberddt274
Pages (from-to)4224-4232
Number of pages9
JournalHuman Molecular Genetics
Issue number20
Publication statusPublished - 1 Oct 2013
Externally publishedYes

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