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Renal Amyloidosis With a Frame Shift Mutation in Fibrinogen A -Chain Gene Producing a Novel Amyloid Protein
Ladan Hamidi Asl,
Juris J. Liepnieks,
Tomoyuki Uemichi,
Jean-Michel Rebibou,
Eve Justrabo,
Dominique Droz,
Christiane Mousson,
Jean-Marc Chalopin,
Merrill D. Benson,
Marc Delpech, and
Gilles Grateau
From EA1501 "Biologie Moléculaire des Cellules Eucaryotes," ICGM-CHU Cochin, Paris, France; the Departments of Medical and Molecular Genetics and Medicine, Indiana University School of Medicine, and Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN; the Service de Néphrologie, Hôpital Saint-Jacques, Besançon, France; the Service de Néphrologie, Laboratoire d'Anatomie Pathologique, Hôpital du Bocage, Dijon, France; the Laboratoire de Pathologie Rénale, Hôpital Necker, Paris, France; and the Service de Médecine Interne, Hôtel Dieu de Paris, Paris, France.
A French kindred with autosomal dominant hereditary renal amyloidosis was found to have a novel mutation in the fibrinogen A -chain gene. In this kindred, renal disease appeared early in life and led to terminal renal failure at an early age. Renal transplantation resulted in rapid destruction of the allograft by amyloid deposition within 2 years. Amyloid fibril protein isolated from a transplanted kidney was found to contain a novel, hybrid peptide of 49 residues whose N-terminal 23 amino acids were identical to residues 499 to 521 of normal fibrinogen A-chain. The remainder of the peptide (26 residues) represented a completely new sequence for mammalian proteins. DNA sequencing documented that the new sequence was the result of a single nucleotide deletion at position 4897 of the fibrinogen A-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 amyloid fibril protein, ie, N-terminal fibrinogen sequence and C-terminal novel sequence, are presently unknown. However, the early onset and rapid reoccurrence of amyloid in renal transplants is unlike the clinical course with other amyloid proteins having single amino acid substitutions that give hereditary renal amyloidosis. Liver transplantation to stop synthesis of this abnormal hepatic derived protein should be considered early in the course of the disease.
Blood, Vol. 90 No. 12 (December 15), 1997:
pp. 4799-4805
© 1997 by The American Society of Hematology.
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