Title: The molecular basis of renal amyloidosis in Irish-American and Polish-Canadian kindreds (1)
Authors: T. Uemichi, J.J. Liepnieks, F. Alexander, and M.D. Benson (Indiana University School of Medicine, Indianapolis, IN, USA and Department of Laboratory Medicine, Calgary General Hospital, Calgary, Canada)
Journal: QJM: An International Journal of Medicine (1996)
Hereditary amyloidosis of an unusual form has been reported in two separate kindreds; one was Polish-Canadian and the other was Irish-American (Am J Med 1975; 59:121 and Trans Assoc Am Physicians 1981; 94: 211). In both kindreds, affected members developed hypertension and nephrotic syndrome due to amyloidosis in their forties or fifties, but the genetic background responsible for the condition has been left undetermined. To identify the genetic defect in these kindreds, a portion of exon 5 of the fibrinogen a-chain gene in members of these kindreds was examined for a mutation by single-strand conformation polymorphism analysis and direct DNA sequencing. DNA analyses revealed an A->T transversion at the second base of codon 526 of the fibrinogen a-chain gene in both of these kindreds. Analysis of DNA polymorphisms in the fibrinogen a-chain gene locus (TCTT repeat in intron 3, Rsal site in exon 5, and Taql site in the 3' flanking region of the gene) showed the haplotype B5-ftsa/( + )- Taql(-) for the Val 526 mutant gene in both kindreds studied here, as well as in two kindreds previously described (J Clin Invest 1994; 93: 731). The fibrinogen a-chain gene mutation (Val 526) is the genetic defect responsible for hereditary renal amyloidosis in these two kindreds, and the mutant genes in the Val 526 kindreds may have been derived from a single founder.Here is a link to the PDF of the article, if you'd like to follow along: http://qjmed.oxfordjournals.org/content/89/10/745.full.pdf
This article reports on the DNA analysis of members of two kindreds that were previously reported to have hereditary renal amyloidosis, before the genetic mutation had been identified. These are the kindreds reported in the 1975 article by Alexander and Atkins (2) and the 1981 article by Mornaghi, et al (3). I don't have either of those articles but I briefly discussed them on February 24, 2013 and March 5, 2013. [Update: Those articles have now been obtained and were reviewed on August 30, 2013 and September 6, 2013.]
The Methods section of this article discusses the laboratory procedures used to detect the mutation in the fibrinogen A alpha gene. In the end, they compared the abnormal patterns found in members of these two families to the patterns found in patients with each of the three known fibrinogen mutations at the time (Arg554Leu, Glu526Val, and the frame shift mutation 4904delG). They found that both of these families carry the Glu526Val mutation.
The Discussion section of the article gives an overview of the three known fibrinogen mutations at the time, and it also includes a paragraph about treatment that mentions liver transplant as being potentially curative. Then the table shown below is presented, which compares the four known kindreds with the Glu526Val mutation as of the writing of this article. Families S and L are the two kindreds discussed in this article, and families D and R are the two kindreds in which the Glu526Val mutation was first discovered.
- At this point (1996), this mutation has not been found in anyone living in Europe, but that is likely to change since three of the four kindreds have Irish ancestry.
- This mutation has been detected in 39 people, with 18 people affected and 21 asymptomatic.
- Speaking of symptoms, note that the clinical features are identical among all four kindreds.
- The age of onset for patients in these four kindreds ranges from a low of 42 to a high of 66.
The article closes with something really interesting I noticed for the first time while reading it for this review, and I'll try to explain it here without going into the details and getting the science all wrong. There are techniques that can be used to do a closer analysis of DNA than just determining the sequence of nucleic acid bases (represented by the letters C, A, G and T). By comparing certain sections of DNA across populations of people they can determine with some accuracy whether or not two people have a "recent" common ancestor. (Yes, if you go back far enough any two people have a common ancestor.) Taken a step further, they can compare the DNA of two people with the same genetic mutation and determine with some accuracy whether their mutations came from the same ancestor or evolved independently.
For some of the other familial amyloidosis mutations they have determined that the mutation likely evolved independently in at least two individuals. But based on this closer DNA analysis on individuals from all four known kindreds with the fibrinogen Glu526Val mutation, it looks like all four of these kindreds have a common ancestor. Given the fact that there are three kindreds with Irish ancestry and one with Polish ancestry, the missing link connecting two or more of these kindreds might be found in Europe.
So as of 1996 there are three known mutations in the fibrinogen A alpha chain that cause hereditary renal amyloidosis. At this point the most common mutation is Glu526Val, which has been detected in 39 people in four different kindreds, all living in the North America. The clinical symptoms commonly associated with this mutation are starting to come into focus, and the age of onset has a fairly large range.
In the next two articles we'll discover yet another fibrinogen mutation, then we'll finally start talking about treatment.
(1) Uemichi T, Liepnieks JJ, Alexander F, Benson MD: The molecular basis of renal amyloidosis in Irish-American and Polish-Canadian kindreds. QJM 89:745, 1996
(2) Alexander, F., and E. L. Atkins. 1975. Familial renal amyloidosis, case reports, literature review and classification. Am. J. Med. 59:121-128.
(3) Mornaghi, R., P. Rubinstein, and E. C. Franklin. 1981. Studies on the pathogenesis of a familial form of renal amyloidosis. Trans. Assoc. Am. Phys. 94:21 1-216.