Genetic, cytogenetic and physical refinement of the autosomal recessive CMT linked to 5q31-q33: exclusion of candidate genes including EGR1

Charcot-Marie-Tooth disease is an heterogeneous group of inherited peripher al motor and sensory neuropathies with several modes of inheritance: autoso mal dominant, X-linked and autosomal recessive. By homozygosity mapping, we leave identified, in the 5q23-q33 region, a third locus responsible for an autosomal recessive form of demyelinating CMT. Haplotype reconstruction an d determination of the minimal region of homozygosity restricted the candid ate region to a 4 cM interval. A physical map of the candidate region was e stablished by screening YACs for microsatellites used for genetic analysis. Combined genetic, cytogenetic and physical mapping restricted the locus to a less than 2 Mb interval on chromosome 5q32, Seventeen consanguineous fam ilies with demyelinating ARCMT of various origins were screened for linkage to 5q31-q33. Three of these seventeen families are probably linked to this locus, indicating that the 5q locus accounts for about 20% of demyelinatin g ARCMT. Several candidate genes in the region were excluded by their posit ion on the contig and/or by sequence analysis. The most obvious candidate g ene, EGR1, expressed specifically in Schwann cells, mapped outside of the c andidate region and no base changes were detected in two families by sequen cing of the entire coding sequence.