Thursday, April 18, 2013

Article Review (1997) - Renal Amyloidosis With a Frame Shift Mutation in a Fibrinogen A Alpha Chain Gene Producing a Novel Amyloid Protein

The subject of this article review is another new mutation in the fibrinogen A alpha gene, discovered in a French kindred. (Note that Dr. Benson is one of the authors again.) This is another frame shift mutation with a much earlier age of onset.

Authors: 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

Journal: Blood (1997)

A French kindred with autosomal dominant hereditary renal amyloidosis was found to have a novel mutation in the fibrinogen A alpha-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 alpha-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 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 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.
Here is a link to the PDF of this article if you would like to follow along:

This article begins with a brief overview of what was known at the time (1997) about hereditary amyloidosis. Then it describes the current case, which is the first French kindred with a fibrinogen mutation causing hereditary renal amyloidosis. The propositus developed kidney issues in 1984 at the age of 31. He was diagnosed with AL amyloidosis and underwent the chemotherapy for AL amyloidosis that was available at the time. He received a kidney transplant in 1988 at the age of 35. A biopsy of the transplanted kidney showed amyloidosis only two years after the transplant, and that kidney was removed in 1995.

The propositus' son developed kidney issues in 1992 at the age of 12. (Yes, 12 years old.) A renal biopsy confirmed amyloid deposits, but his blood work and bone marrow biopsy were not consistent with AL amyloidosis. His kidney failure progressed rapidly such that he began peritoneal dialysis at the age of 13 and received a kidney transplant at the age of 15. He began developing kidney issues only one year after the kidney transplant, and a renal biopsy confirmed amyloidosis in the transplanted kidney. Blood clotting times were normal in both patients.

The Materials and Methods section of this article, like others I have previously reviewed, goes into detail describing the laboratory methods used. In this case they isolated the amyloid fibrils from the transplanted kidney that was removed from the propositus, isolated the amyloid protein from those fibrils, and then did various tests in order to analyze the DNA of the proteins and both patients.

The Results section describes the mutation that was found, which was another frame shift mutation. The previous frame shift mutation (4904delG, reviewed here) occurred at position 4904 of the fibrinogen A alpha-chain gene. This new mutation occurred slightly earlier due to a deletion at position 4897. (For reference, the Glu526Val mutation is a substitution at position 4909.) Since this frame shift mutation starts a little earlier than the one previously described, this one has a few more amino acids that are different at the beginning of the mutated string, but once it gets past position 4904 the two mutations are identical, including the premature stop. This mutation is referred to as 4897delT, since the nucleotide "T" at position 4897 is deleted.

The Discussion section of the article reviews what is currently known about fibrinogen mutations that cause hereditary renal amyloidosis, and then compares this mutation to the others. The age of onset for this mutation is definitely at the younger end of the range, with the previously youngest reported age of onset being 24 in a patient with the Arg554Leu mutation. The rapid reoccurrence of amyloid in the transplanted kidneys of both of these patients indicates that a kidney transplant may not be a good form of treatment. The article then states that liver or combined liver/kidney transplants should be considered, since fibrinogen production is essentially limited to the liver.


So as of 1997, four fibrinogen mutations have been reported that cause hereditary renal amyloidosis. Two mutations are substitutions (Arg554Leu and Glu526Val) and two are frame shift mutations due to deletions (4904delG and 4897delT). With this latest mutation we have our first European patients, but the Glu526Val mutation is currently the most common and has still not been reported in Europe. However, things get interesting in Europe with the next two articles.

[11-5-13: Corrected one spelling error.]


(1) Hamidi Asl L., Liepnieks J.J., Uemichi T., Rebibou J.M., Justrabo E., Droz D., Mousson C., Chalopin J.M., Benson M.D., Delpech M., Grateau G. Renal amyloidosis with a frame shift mutation in fibrinogen a α-chain gene producing a novel amyloid protein. Blood. 1997;90:4799–4805.

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