Detection of DNA duplications in charcot-marie-tooth type 1 (CMT1) patients by DNA analysis

Abstract

Charcot-Marie-Tooth neuropathy (CMT), also known as Hereditary Motor and Sensory Neuropathy (HMSN), is a heterogeneous group of inherited diseases of peripheral nerves. It is estimated that 112500 persons have a form of CMT. CMT1, which typically shows dominant inheritance, has been associated with at least 4 distinct loci: The CMTlA locus on chromosome 17, the CMTlB locus on chromosome 1, the CMTlC locus, yet unmapped, and the CMTX locus on the X chromosome. CMTlA appears to be the most prevalent form of CMTl and is associated with a 1.5 Mb tandem DNA duplication of p 11.2-p12 locus on chromosome 17. The duplications in various ethnic groups have similar frequencies suggesting that it is the most prevalent cause of CMTlA. Unequal crossing over during male gametogenesis is thought to be the mechanism leading to the CMTlA duplication. Evidence showed the responsibility of dosage effect of the PMP22 gene, which maps within the CMTlA duplication interval, for the disease phenotype. The aim of this study was to accomplish molecular analysis of CMT in Turkey. Since CMTlA is the most common type of CMT for which the genetic defect has already been identified, the analysis was started by detection of duplication in CMTl patients. Detection of the duplication is an important requirement for the differential diagnosis of CMTlA, especially for patients with clinical symptoms similar to those typical for other peripheral neuropathies. In this study, sixty nine per cent of CMTl patients were found to carry the duplication by using a CA repeat polymorphism. Presence of the duplications in these patients was confirmed by Southern analysis using two different markers. These markers were shown to be highly informative for the detection of duplications, correlating with the previously published data for other populations.