2 AUTOSOMAL-DOMINANT NEUROPATHIES RESULT FROM RECIPROCAL DNA DUPLICATION DELETION OF A REGION ON CHROMOSOME-17/

Charcot-Marie-Tooth disease type 1A (CMT1A) is a common autosomal domi nant demyelinating neuropathy that is associated with a 1.5 megabase ( Mb) tandem DNA duplication in chromosome 17p11.2-p12. Hereditary neuro pathy with liability to pressure palsies (HNPP, tomaculous neuropathy) is another less frequently diagnosed autosomal dominant neuropathy an d is associated with a 1.5 Mb deletion in chromosome 17p11.2-12. Meiot ic unequal crossover Is a proposed mechanism for the generation of bot h the duplication in CMT1A and the deletion in HNPP. CMT1A:REP is a re peat that flanks the region which is duplicated/deleted in CMT1A/HNPP. The CMT1A-REP repeat sequence may mediate unequal crossover through m isalignment of the homologous, repeated sequences. Three copies of the CMT1A-REP repeat are present on stably inherited CMT1A duplication ch romosomes. In this report, molecular analysis in multiple patients det ected three copies of the CMT1A-REP sequence on both inherited and de novo CMT1A duplication chromosomes, and one copy of the CMT1A-REP repe at on the deleted chromosome in both inherited and de novo HNPP. These observations support the hypothesis that a reciprocal recombination m echanism involving the CMT1A-REP is responsible for the generation of both the duplicated and deleted chromosomes, and document the first ex amples in humans of Mendelian syndromes resulting from the reciprocal products of unequal exchange involving large intra-chromosomal segment s.