Notes and emendations (August 31, 1999) by Webmaster Curtis L. Atkin (70373.523@compuserve.com) are [bracketed].
In earlier issues of the Newsletter, Dr Curtis Atkin has explained how hereditary nephritis is transmitted in families and how the gene responsible for the condition lies on the X-chromosome. In 1972, electron microscopy with its enormous magnification brought a powerful new method to examine the kidney. For the first time, abnormalities were seen in the glomerular basement membrane, the delicate membrane which forms the scaffolding of the tiny blood vessels in the kidney. Instead of being a fine film of uniform thickness, this membrane was thickened, and split into a number of layers. Often there were dense granules lying between the layers. Until recently no-one had any idea how the hereditary nephritis gene brings about this damage to the glomerular basement membrane, damage which results in blood in the urine and eventually in kidney failure.
Minnesota, like the intermountain west, has many families with hereditary nephritis, Doctors at the University of Minnesota have been studying hereditary nephritis for almost as long as those at the University of Utah. In October this year, Dr Robert Vernier from the University of Minnesota visited the University of Utah and discussed recent work that he has done with glomerular basement membranes of sufferers from hereditary nephritis. This work stemmed from the chance observation that a patient with hereditary nephritis who had received a renal transplant developed a second form of kidney disease in the transplanted kidney. This second disease was of a most unusual type that occurs when the body forms antibodies against one of its own parts, in this case the glomerular basement membrane. This happened because the patient's antibody forming cells had never seen normal glomerular basement membrane until a normal kidney was transplanted into the patient. This observation was the first hint that, instead of having something extra in the glomerular basement membrane, as might be expected from the extra layers and thickness, there is actually something missing in hereditary nephritis. Dr Vernier's group as well as researchers in other universities began to look at the various proteins which make up the glomerular basement membrane, and soon decided that collagen was the most likely suspect. Collagen is a tough structural protein that occurs throughout the body and gives strength to tissues like tendon, ligaments, bones and skin. The collagen in the glomerular basement membrane is somewhat different from that in most other parts of the body - it is known as Type IV collagen.
By partially digesting the Type IV collagen from the glomerular basement membrane of hereditary nephritis patients, Dr Vernier was able to show that a part of the molecule was lacking - or at least it didn't show up in the normal place in the separation procedures that he used. This is a major step forward in understanding what is going wrong in the chemistry of the kidney proteins in hereditary nephritis, but it still leaves both a lot of unanswered questions and also avenues for further research. One particular difficulty is that the gene for Type IV collagen does not lie on the X-chromosome. We know from Dr Atkin's work that it is the X-chromosome that determines the inheritance of hereditary nephritis in most families. Perhaps there is another substance, controlled by the gene on the X-chromosome that in turn alters the structure of collagen. [Several years after this was written, Dr Karl Tryggvason's group in Finland discovered a new Type IV collagen chain that was encoded on the X chromosome, and the Utah Alport group then found that mutations in that COL4A5 gene did indeed account for X-linked Alport syndrome].
Every step forward in these laborious lines of research brings us closer to a full understanding of the exact way that the hereditary nephritis gene causes nephritis. This knowledge is necessary to work out the best forms of treatment, and eventually ways to prevent progressive kidney damage in hereditary nephritis.