MUTATION ANALYSIS OF THE CHROMOSOME 14Q24.3 DIHYDROLIPOYL SUCCINYLTRANSFERASE (DLST) GENE IN PATIENTS WITH EARLY-ONSET ALZHEIMER-DISEASE

Linkage analysis studies have indicated that the chromosome band 14q24 .3 harbours a major gene for familial early-onset Alzheimer's disease (AD). Recently we localized the chromosome 14 AD gene (AD3) in the 6.4 cM interval between the markers D14S289 and D14S61. We mapped the gen e encoding dihydrolipoyl succinyltransferase (DLST), the E2k component of human alpha-ketoglutarate dehydrogenase complex (KGDHC), in the AD 3 candidate region using yeast artificial chromosomes (YACs). The DLST gene is a candidate for the AD3 gene since deficiencies in KGDHC acti vity have been observed in brain tissue and fibroblasts of AD patients , The 15 exons and the promoter region of the DLST gene were analysed for mutations in chromosome 14 linked AD cases and in two series of un related early-onset AD cases (onset age < 55 years). Sequence variatio ns in intronic sequences (introns 3, 5 and 10) or silent mutations in exonic sequences (exons 8 and 14) were identified. However, no AD rela ted mutations were observed, suggesting that the DLST gene is not the chromosome 14 AD3 gene.