A 1.5-MB DELETION IN 17P11.2-P12 IS FREQUENTLY OBSERVED IN ITALIAN FAMILIES WITH HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathie s. A 1.5-Mb deletion in chromosome 17p11.2-p12 has been associated wit h HNPP. Duplication of the same 1.5-Mb region is known to be associate d with Charcot-Marie-Tooth disease type 1 (CMT1A), a more severe perip heral neuropathy characterized by symmetrically slowed nerve conductio n velocity (NCV). The CMT1A duplication and HNPP deletion appear to be the reciprocal products of a recombination event involving a repeat e lement (CMT1A-REP) that hanks the 1.5-Mb region involved in the duplic ation/deletion. Patients from nine unrelated Italian families who were diagnosed with HNPP on the basis of clinical, electrophysiological, a nd histological evaluations were analyzed by molecular methods for DNA deletion on chromosome 17p. In all nine families, Southern analysis u sing a CMT1A-REP probe detected a reduced hybridization signal of a 6. 0-kb EcoRI fragment mapping within the distal CMT1A-REP, indicating de letion of one copy of CMT1A-REP in these HNPP patients. Families were also typed with a polymorphic (CA)(n) repeat and with RFLPs correspond ing to loci D17S122, D17S125, and D17S61, which all map within the del eted region. Lack of allelic transmission from affected parent to affe cted offspring was observed in four informative families, providing an independent indication for deletion. Furthermore, pulsed-field gel el ectrophoresis analysis of SacII-digested genomic DNA detected junction fragments specific to the 1.5-Mb HNPP deletion in seven of nine Itali an families included in this study. These findings suggest that a 1.5- Mb deletion on 17p11.2-p12 is the most common mutation associated with HNPP.