ORIGIN OF THE DE-NOVO DUPLICATION IN CHARCOT-MARIE-TOOTH DISEASE TYPE1A - UNEQUAL NONSISTER CHROMATID EXCHANGE DURING SPERMATOGENESIS

A 1.5 Mb duplication within 17p11.2 is the major mutation causing both autosomal dominant and sporadic Charcot-Marie-Tooth disease type 1A ( CMT1A). An independent origin for the mutation in each family has been postulated. The proposed genetic mechanism causing the CMT1A duplicat ion is unequal nonsister chromatid exchange at meiosis (unequal crossi ng-over). We studied the parental origin of the duplication in nine ge netically sporadic CMT1A patients and demonstrated that in all cases t he mutation was the product of an unequal nonsister chromatid exchange during spermatogenesis. The fact that only paternal de novo duplicati ons were observed in the sporadic CMT1A patients suggests that male sp ecific factors may be operating during spermatogenesis that either hel p forming the duplication and/or stabilize the duplicated chromosome.