The molecular basis of renal amyloidosis in Irish-American and Polish- Canadian kindreds

Hereditary amyloidosis of an unusual form has been reported in two separatekindreds; one was Polish-Canadian and the other was Irish- American (Am JMed 1975; 59:121 and Trans Assoc Am Physicians 1981; 94:211). In bothkindreds, affected members developed hypertension and nephrotic syndromedue to amyloidosis in their forties or fifties, but the genetic backgroundresponsible for the condition has been left undetermined. To identify thegenetic defect in these kindreds, a portion of exon 5 of the fibrinogenalpha-chain gene in members of these kindreds was examined for a mutationby single-strand conformation polymorphism analysis and direct DNAsequencing. DNA analyses revealed an A-->T transversion at the secondbase of codon 526 of the fibrinogen alpha-chain gene in both of thesekindreds. Analysis of DNA polymorphisms in the fibrinogen alpha-chain genelocus (TCTT repeat in intron 3, Rsal site in exon 5, and Taql site in the3' flanking region of the gene) showed the haplotype B5-Rsal(+)-Taql(-) forthe Val 526 mutant gene in both kindreds studied here, as well as in twokindreds previously described (J Clin Invest 1994; 93:731). The fibrinogenalpha-chain gene mutation (Val 526) is the genetic defect responsible forhereditary renal amyloidosis in these two kindreds, and the mutant genes inthe Val 526 kindreds may have been derived from a single founder.