Structure and expression of the mutant prealbumin gene associated with familial amyloidotic polyneuropathy

We have cloned a chromosomal DNA segment that covers the entire sequence for the mutant prealbumin gene associated with familial amyloidotic polyneuropathy, and determined the sequence of the gene including 581 base-pairs of the 5'-flanking region and 95 base-pairs of the 3'-flanking region, except for the internal portions of the second and third introns. This sequence was aligned with that of the previously determined normal prealbumin gene and both sequences matched perfectly except for a single-base substitution present in the second exon. This substitution is responsible for the transition from valine (GTG) to methionine (ATG) in the mutant prealbumin and creates NsiI and BalI restriction sites in the mutant prealbumin gene. We also analysed prealbumin mRNAs in the livers of a disease-free individual and one with familial amyloidotic polyneuropathy and confirmed that there is no difference in the levels and sizes of the prealbumin mRNAs between the two. As we have demonstrated already that individuals with familial amyloidotic polyneuropathy are heterozygous for the prealbumin gene, carrying one normal and one mutant gene, levels of the two different mRNAs within the liver of an individual with familial amyloidotic polyneuropathy were separately estimated and were demonstrated to be approximately equal.