A locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 1q21.2q21.3

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders tha t affect the peripheral nervous system. Three loci are known for the autoso mal dominant forms of axonal CMT (CMT2), but none have yet been identified for autosomal recessive axonal CMT (ARCMT2). We have studied a large consan guineous Moroccan ARCMT2 family with nine affected sibs. The onset of CMT w as in the 2d decade in all affected individuals who presented with a severe motor and sensory neuropathy, with proximal muscle involvement occurring i n some patients. After exclusion of known loci for CMT2 and for demyelinati ng ARCMT2, a genomewide search was performed. Evidence for linkage was foun d with markers on chromosome Iq. The maximum pairwise LOD score was above t he threshold value of 3.00, for markers D1S514, D1S2715, D1S2777, and D1S27 21, and it reached 6.10 at the loci D1S2777, D1S2721, and D1S2624, accordin g to multipoint LOD-score analysis. These markers defined a region of homoz ygosity that placed the gene in a 4.4-cM interval. Moreover, a recombinatio n event detected in an unaffected 48-year-old individual excludes the D1S50 6 marker, thereby reducing the interval to 1.7 cM. In addition, the PO gene , an attractive candidate because of both its location on chromosome Iq and its role in myelin structure, was excluded by physical mapping and direct sequencing.