title: PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.
abstract: 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.
authors.affiliation: These authors contributed equally to this work.
authors.forename: Hamid
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authors.lastname: Zavadakova
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authors.lastname: Vaz Pato
authors.forename: Nuno
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authors.forename: Jennifer
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authors.forename: Giulia
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authors.lastname: Venturini
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Médard
authors.forename: Edward
authors.initials: E
authors.lastname: Makowski
authors.forename: Ludger
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authors.lastname: Schöls
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authors.lastname: Claeys
authors.forename: Claudia
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authors.lastname: Roos
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authors.lastname: Weis
authors.forename: Odile
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authors.lastname: Dubourg
authors.forename: José
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authors.lastname: Leal Loureiro
authors.forename: Giovanni
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authors.lastname: Stevanin
authors.forename: Gérard
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authors.lastname: Said
authors.forename: Anthony
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authors.lastname: Amato
authors.forename: Jay
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authors.lastname: Baraban
authors.forename: Eric
authors.initials: E
authors.lastname: LeGuern
authors.forename: Jan
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authors.lastname: Senderek
authors.forename: Carlo
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authors.forename: Roman
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authors.lastname: Chrast
mesh_terms: D000328:Adult; D017668:Age of Onset; D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D018389:Codon, Nonsense; D005260:Female; D005808:Genes, Recessive; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics; D020125:Mutation, Missense; D009457:Neuroglia / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D020662:Guanine Nucleotide Exchange Factors; C522397:PLEKHG5 protein, human; C511269:Syx protein, mouse