The familial amyloidotic polyneuropathies (FAP's) and Senile Systemic (cardiac) Amyloidosis have been shown to be caused by the deposition of thyroxine-binding prealbumin (transthyretin)-related molecules in various tissues, notably peripheral and autonomic nerves, heart, gastrointestinal tract, occasionally lungs, almost always in blood vessels. In some of the described kindreds, substitutions in the normal amino acid sequence of transthyretin have been reported. It is likely that these substitutions, usually related to a single base change (hence likely to reflect a point mutation), result in instability of the prealbumin molecule under physiologic conditions with resultant tissue deposition. It is now possible to identify many of these mutant prealbumins by restriction fragment length polymorphism (RFLP) analysis, allowing both ante-natal and presymptomatic diagnosis. Since the diseases are autosomal dominant, the presence of the RFLP uniformly presages the development of the disease. In the ante-natal case, a positive assay allows the parents the option of interrupting pregnancy. In individuals who carry the gene but are asymptomatic, no procedure with demonstrable therapeutic efficacy can be offered. Our application proposes to: a) utilize specific RFLP's we have found to determine the presence of the aberrant gene in asymptomatic children at risk for inheriting the gene, b) pinpoint the base changes associated with the previously undescribed molecular abnormalities, and c) develop a model for the disease(s) by inserting a mutant prealbumin gene into the germline of a suitable mouse strain and breeding a line of transgenic mice constitutively or inducibly expressing the abnormal gene product in large amounts. Our assumption is that such animals will predictably develop the disease(s) and thus allow proposed therapeutic interventions to be tested in a valid experimental setting. At the moment, no such model exists.
