THE GENETIC-DEFECT IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-2A MAPS NEXT TO THE CENTROMERE OF CHROMOSOME-10

  • 1 March 1990
    • journal article
    • research article
    • Vol. 46  (3) , 624-630
Abstract
Multiple endocrine neoplasia type 2A (MEN2A) is a rare cancer syndrome that is inherited in a apparently autosomal dominant fashion. Previous linkage studies had assigned the MEN2A locus to chromosome 10 in the pericentromeric region. We recently have described several new easily scorable RFLPs for the chromosome 10-specific alpha satellite DNA (the D10Z1) locus that is known, on the basis of previous in situ hybridization experiments, to lie at the centromere. We report here tight linkage between MEN2A and D10Z1, as demonstrated by a maximum lod score of 12.02 at the recombination frequency of zero (1-lod-unit support interval 0-4 cM), indicating that the genetic defect in MEN2A lies in the immediate vicinity of the centromere. By means of a set of ordered polymorphic DNA markers from the pericentromeric region, multipoint as well as pairwise linkage analyses place the MEN2A locus at the middle of a small region (.apprx.11 cM) bracketing the centromere with FNRB (at 10p11.2) and RBP3 (at 10q11.2) on either side, providing further support for the centrometric location of the MEN2A locus. Marked sex difference in recombination frequencies exists in this pericentromeric region: significantly (P < .01) more female than male crossovers were observed across all of the adjacent intervals D10S24-FNRB, FNRB-D10Z1, and D10Z1-RBP3. However, a sex difference was not seen in the 7-cM interval from RBP3 to D10S5, suggesting that large variation in the sex difference in recombination cna occur over small chromosomal regions. Proper clinical applications of these DNA markers in genetic counseling to determine the genotypes at the disease locus for those at-risk members in informative afflicted families must therefore take into account the implications imposed by the large and highly significant sex effect on recombination in the MEN2A region.