title: Mutation analysis of MFN2, GJB1, MPZ and PMP22 in Italian patients with axonal Charcot-Marie-Tooth disease.
abstract: Charcot-Marie-Tooth (CMT) diseases include a group of clinically heterogeneous inherited neuropathies subdivided into demyelinating (CMT1), axonal (CMT2) and intermediate CMT forms. CMTs are associated with different genes, although mutations in some of these genes may cause both clinical pictures. To date, more than 50 CMT genes have been identified, but more than half of the cases are due to mutations in MFN2, MPZ, GJB1 and PMP22. The aim of this study was to estimate the frequency of disease mutations of these four genes in the axonal form of CMT in order to evaluate their effectiveness in the molecular diagnosis of CMT2 patients. A cohort of 38 CMT2 Italian subjects was screened for mutations in the MFN2, MPZ and GJB1 genes by direct sequencing and for PMP22 rearrangements using the MLPA technique. Overall, we identified 15 mutations, 8 of which were novel: 11 mutations (28.9 %) were in the MFN2 gene, 2 (5.3 %) in MPZ and 2 (5.3 %) in PMP22. No mutations were found in GJB1. Two patients showed rearrangements in the PMP22 gene, which is commonly associated with CMT1 or HNPP phenotypes thus usually not tested in CMT2 patients. By including this gene in the analysis, we reached a molecular diagnosis rate of 39.5 %, which is one of the highest reported in the literature. Our findings confirm the MFN2 gene as the most common cause of CMT2 and suggest that PMP22 rearrangements should be considered in the molecular diagnosis of CMT2 patients.
authors.affiliation: Department of Biology, University of Padova, Padua, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Bergamin
authors.forename: Francesca
authors.initials: F
authors.lastname: Boaretto
authors.forename: Chiara
authors.initials: C
authors.lastname: Briani
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
authors.forename: Mario
authors.initials: M
authors.lastname: Cacciavillani
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Maria
authors.initials: M
authors.lastname: Muglia
authors.forename: Andrea
authors.initials: A
authors.lastname: Vettori
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vazza
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Mostacciuolo
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002607:Charcot-Marie-Tooth Disease / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020440:Gene Duplication; D005799:Genes, Dominant; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D007223:Infant; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense; D018993:Myelin P0 Protein / Q000235:genetics*; D009185:Myelin Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion; D063189:Symptom Assessment; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D020558:GTP Phosphohydrolases; D024101:Mitochondrial Proteins; D018993:Myelin P0 Protein; D009185:Myelin Proteins; D000097002:Gap Junction beta-1 Protein; C560547:MPZ protein, human; C073687:PMP22 protein, human; C470018:MFN2 protein, human