Monday, September 30, 2013

Article Review (1993) - Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain

Today's article under review is another one that was previously reviewed but only recently acquired. It was the first article discussed in the March 20, 2013 post, when I only had the abstract. This 1993 article is very important in the history of fibrinogen amyloidosis since it describes the first fibrinogen amyloidosis mutation that was discovered, so I will go ahead and write a full review here as if the previous one were never done.

Title: Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain (1)

Authors: Benson MD, Liepnieks J, Uemichi T, Wheeler G, Correa R. (Department of Medicine, Indiana University School of Medicine, Indianapolis, USA)

Journal: Nature Genetics (1993)


Three members of a family who died with renal amyloidosis were found to share a single nucleotide substitution in the fibrinogen alpha-chain gene. The predicted arginine to leucine mutation (Arg554Leu) was proven by amino acid sequence analysis of amyloid fibril protein isolated from postmortem kidney of an affected individual. Direct genomic DNA sequencing and restriction fragment length polymorphism analysis demonstrated that all three affected individuals had the guanine to thymine 4993 transversion.
This is the first demonstration of hereditary amyloidosis associated with a variant fibrinogen alpha-chain. Variants of circulating fibrinogen may be the cause of a number of systemic amyloidoses with primarily renal involvement.

The article begins with an overview of the types of hereditary amyloidosis that were known at the time. It states that a number of families have been identified with a hereditary form of amyloidosis that is autosomal dominant where the principal organ involved is the kidney, and the amyloidosis is not caused by mutations in any of the proteins already known to cause amyloidosis.

The propositus (first identified family member) was a 50 year old Peruvian male. He developed kidney issues at the age of 36 and received a kidney transplant at the age of 40. Eight years later a renal biopsy showed amyloid deposits (primarily in the glomeruli), and he received a second kidney transplant at the age of 50. He died soon after the second kidney transplant due to septicaemia. At autopsy, his original kidneys showed much less amyloid deposition than the kidney that was first transplanted at the age of 40. There were also some amyloid deposits in the spleen but not in the liver.

A sister of the propositus died at the age of 28. She had nephrotic syndrome, and a kidney biopsy showed amyloid deposits in the glomeruli. Another sister was over 50 years old and in good health at the time this article was published.

The propositus had two sons and one daughter. One son developed azotemia at age 24, and a kidney biopsy showed amyloid deposits in the glomeruli. He died shortly after being placed on hemodialysis. The daughter and the other son of the propositus were reportedly healthy at the time this article was published.

The next section gives a technical description of how it was determined the propositus had a fibrinogen mutation. I don't understand much of it, but the oversimplified version is that after this patient's death, they analyzed a small quantity of tissue from the first transplanted kidney which had been transplanted ten years prior to his death. They isolated 7.3 mg of protein from 200 mg of kidney tissue, and then analyzed that to determine what specific protein or proteins it matched. They found that it matched part of the fibrinogen alpha-chain with the exception of one location.

This particular mutation substituted leucine for arginine at amino acid position 554 of the fibrinogen alpha chain, so it is referred to as Arg554Leu. (The most common fibrinogen amyloidosis mutation, Glu526Val, substitutes valine for glutamic acid at amino acid position 526.)

The final section of the article mentions that fibrinogen is involved in the final phase of blood coagulation, and many fibrinogen mutations have already been discovered in individuals with blood clotting disorders. Since fibrinogen is present in the blood at a relatively high concentration, it is not surprising that it could be involved in the formation of amyloid fibrils. Given the fact that other proteins have multiple mutations that can cause amyloidosis, the article states that it is likely that other fibrinogen mutations will be discovered to cause amyloidosis.


The main similarities between this mutation and the Glu526Val mutation are the presence of amyloid deposits in the glomeruli of the kidneys, and the fact that the kidneys are the primary organ affected. The main difference, based on the kindred described in this article, is that the age of onset is certainly much younger than the average age of onset with the Glu526Val mutation.

One other statement from the article that got my attention was the fact that the transplanted kidney had much heavier amyloid deposition than the original kidneys. At the time of death the patient's original kidneys had been in place for 50 years, whereas the transplanted kidney had only been in place in this patient's body for 10 years. We probably cannot draw any definite conclusions just from this patient, but it does make me wonder if something accelerates the production of amyloids as a person ages, or, since we do not know the age of the kidney donor, does something make the kidneys more susceptible to amyloid deposits as they get older? We will see in later articles that recipients of a kidney transplant who do not also get a liver transplant can expect the transplanted kidney to eventually be affected by amyloid, but the point at which it becomes clinically significant varies over a very wide range.

Now that the first fibrinogen mutation causing familial amyloidosis has been discovered, we only have to wait a year for the next mutation. That article was published in 1994 and reviewed in the March 20, 2013 blog post. The next article for review takes us all the way to 2003, describing the first patient to receive a liver-kidney transplant for fibrinogen amyloidosis.


(1) Benson MD, Liepnieks J, Uemichi T, Wheeler G, Correa R. Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet 1993; 3: 252-255.

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