Towards the Identification of the Gene for Chromosome 17-Linked FTDP

M. Hutton

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Eight families with fronto-temporal dementia and parkinsonism (FTDP) have been definitively linked (lod >3.0) to the same region of chr17q21-22 and at least a further 7 kindreds with similar syndromes display evidence of linkage to the same region. Recombination events in the FTDP-17 families have identified a 2cM critical region in which the gene for this disorder is likely to occur. Clinical features of the disease in each of these families includes presenile age of onset (usually below 65 yrs) and early personality change progressing to dementia. Extrapyramidal signs with parkinsonian features have been described in most families although the degree to which this symptom appears has been reported to vary markedly. At autopsy patients with FTDP-17 display marked atrophy of the frontal and temporal lobes with cell loss, white and gray matter gliosis and neuropil vacuolation. Balloon neurons and tau positive inclusions are also variably observed in most kindreds.

FTDP-17 consortium Mayo Clinic Jacksonville, FL32224, USA

The significant variability in both the clinical and neuropathological features in the families has made it impossible to accurately determine the prevalence of FTDP-17 and we no virtually nothing about the etiology of this disease. As a result the identification of the causative genetic lesion has become a major goal of research in this area. As part of our multi-center effort to identify the FTDP-17 gene we have generated a contiguous physical map of the minimal candidate region in YAC, PAC, P1 and cosmid clones and have extensively mapped known genes and EST clusters from the Human Transcript Map. Exon trapping experiments have further increased the number of genes known to lie in the critical region. We are presently generating "full-length" cDNA sequences for each of the identified candidate genes and then sequencing these for mutations in each of the six FTDP-17 families available to our consortium. Our progress in this positional cloning effort will provide the major focus of my presentation.