RENAL AMYLOIDOSIS WITH A FRAME-SHIFT MUTATION IN FIBRINOGEN A-ALPHA-CHAIN GENE PRODUCING A NOVEL AMYLOID PROTEIN

A French kindred with autosomal dominant hereditary renal amyloidosis was found to have a novel mutation in the fibrinogen Aa-chain gene. In this kindred, renal disease appeared early in life and led to termina l renal failure at an early age. Renal transplantation resulted in rap id destruction of the allograft by amyloid deposition within 2 years. Amyloid fibril protein isolated from a transplanted kidney was found t o contain a novel, hybrid peptide of 49 residues whose N-terminal 23 a mino acids were identical to residues 499 to 521 of normal fibrinogen A alpha-chain. The remainder of the peptide (26 residues) represented a completely new sequence for mammalian proteins. DNA sequencing docum ented that the new sequence was the result of a single nucleotide dele tion at position 4897 of the fibrinogen A alpha-chain gene that gives a frame-shift at codon 522 and premature termination at codon 548. The contributions toward fibrillogenesis of the two portions of the amylo id fibril protein, ie, N-terminal fibrinogen sequence and C-terminal n ovel sequence, are presently unknown. However, the early onset and rap id reoccurrence of amyloid in renal transplants is unlike the clinical course with other amyloid proteins having single amino acid substitut ions that give hereditary renal amyloidosis. Liver transplantation to stop synthesis-of this abnormal hepatic derived protein should be cons idered early in the course of the disease. (C) 1997 by The American So ciety of Hematology.