Human transthyretin (prealbumin) gene and molecular genetics of familial amyloidotic polyneuropathy.

Transthyretin (TTR, also called prealbumin) is a plasma protein produced in liver. The variant types of TTR are known to be closely associated with familial amyloidotic polyneuropathy (FAP), an autosomal dominant genetic disorder. This article summarizes, together with some new data, our current knowledge on FAP from the view point of molecular genetics. As an initial step towards understanding the disease at the DNA level, the complete nucleotide sequence of the human TTR gene (-7 kb to 7 kb; 1 kb = 10(3) bases) was determined and analyzed. The gene is located on chromosome 18 q12.1 and consists of four exons. Homology search revealed that there exist several possible regulatory signals in the 5' flanking region of the gene, including the binding sites for liver-specific nuclear factors HNF-1, 3, 4 and C/E BP, which have been previously identified in mouse TTR gene. Sequence analysis enabled us to identify all the mutations related to various types of FAP. The mutations were shown to be almost completely linked to FAP and it has become possible to diagnose FAP even at presymptomatic (prenatal) stages by recombinant DNA technology, with a high reliability. Haplotype analysis of FAP families using DNA polymorphic markers in the TTR locus suggested that the Val30----Met mutation closely related to type I FAP, the most common type of FAP, has frequently recurred in the human population to generate FAP families of independent origin. Although the primary cause of FAP has become clear, extensive screening of FAP families in various locations suggested that the expression of FAP is a complicated process and affected by some unknown factors (other than TTR).(ABSTRACT TRUNCATED AT 250 WORDS)