title: Copy number variation upstream of PMP22 in Charcot-Marie-Tooth disease.
abstract: In several individuals with a Charcot-Marie-Tooth (CMT) phenotype, we found a copy number variation (CNV) on chromosome 17p12 in the direct vicinity of the peripheral myelin protein 22 (PMP22) gene. The exact borders and size of this CNV were determined by Southern blot analysis, MLPA, vectorette PCR, and microarray hybridization analyses. All patients from six apparently unrelated families carried an identical 186-kb duplication different from the commonly reported 1.5-Mb duplication associated with CMT1A. This ancestral mutation that was not reported in the human structural variation database was only detected in affected individuals and family members. It was absent in 2124 control chromosomes and 40 patients with a chronic inflammatory demyelinating polyneuropathy (CIDP) and therefore should be regarded as causative for the disease. This variant escapes most routine diagnostic screens for CMT1A, because copy numbers of PMP22 probes were all normal. No indications were found for the involvement of the genes that are located within this duplication. A possible association of this duplication with a mutation in the PMP22 coding regions was also excluded. We suggest that this CNV proximal of the PMP22 gene leads to CMT through an unknown mechanism affecting PMP22 expression.
authors.affiliation: Neurogenetics Lab, Department of Neurogenetics K2-213, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. m.a.weterman@amc.uva.nl
authors.forename: Marian A J
authors.initials: MA
authors.lastname: Weterman
authors.forename: Fred
authors.initials: F
authors.lastname: van Ruissen
authors.forename: Marit
authors.initials: M
authors.lastname: de Wissel
authors.forename: Lou
authors.initials: L
authors.lastname: Bordewijk
authors.forename: Johnny P A
authors.initials: JP
authors.lastname: Samijn
authors.forename: W Ludo
authors.initials: WL
authors.lastname: van der Pol
authors.forename: Farid
authors.initials: F
authors.lastname: Meggouh
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
mesh_terms: D000328:Adult; D015139:Blotting, Southern; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D020090:Chromosome Segregation; D055028:Comparative Genomic Hybridization; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D020440:Gene Duplication; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008868:Microtubule Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D008868:Microtubule Proteins; D009185:Myelin Proteins; C073687:PMP22 protein, human; C044103:tektins