LINKAGE OF THE GENE FOR THE TRIPLE-A-SYNDROME TO CHROMOSOME 12Q13 NEAR THE TYPE-II KERATIN GENE-CLUSTER

The triple A or Allgrove's syndrome (MIM231550) is an autosomal reces sive disease characterized by the triad of adrenocorticotropic hormone (ACTH) resistant adrenal insufficiency, achalasia and alacrima, Since its first description by Allgrove al al, (1978) more than 70 cases fr om all over the world have been reported, The syndrome manifests itsel f during the first decade of life with severe hypoglycaemic episodes w hich can cause sudden death, The frequent association with neurologica l disorders presenting as a mixed pattern of upper and lower motor neu ropathy, sensory impairment, autonomic neuropathy and mental retardati on may result in a severely disabling disease, As an additional featur e some patients have hyperkeratosis of their palms and soles, We have performed a systematic genome linkage scan in eight triple A families of which three were consanguineous [including the large highly inbred kindred described by Moore al al. (1991)], We obtained conclusive evid ence for linkage of the triple A syndrome locus to markers on chromoso me 12q13 (D12S368, theta(max) = 0, Z(max) = 10.81) with no indication of genetic heterogeneity, Haplotype and multipoint analyses suggest th at the gene is located on a chromosomal segment flanked by the markers D12S1629 and D12S312 which are 6 cM apart, This region harbors the ty pe II keratin gene cluster, and potential candidate genes include SCN8 A and HOXC genes.