Recent explosive growth in our knowledge about the different types and genetic causes of hereditary nephritis has aroused the interest of 15-20 research and diagnostic centers. I hope to clarify the different resources now available.
RESEARCH STUDY: The Alport Syndrome/Hereditary Nephritis Study at University of Utah is currently staffed by Curtis L. Atkin PhD, David F. Barker PhD, Joyce Denison PhD, Pamela Fain PhD, and Martin C. Gregory MD. We are collaborating closely with the group of Karl Tryggvason MD PhD, Jing Zhou MD PhD, and others at University of Oulu, Finland. We are actively studying 78 kindreds from all over the North American Continent. To date we have located the genetic causes of hereditary nephritis in 20 kindreds to abnormalities within or near the gene COL4A5 on the X chromosome. In some cases we have determined the actual chemical nature of mutations in DNA of the COL4A5 gene. We believe that X-linked hereditary nephritis in other families is also caused by abnormalities within just that gene.
We will call members of families already under study should we desire their participation. Any persons who may want further evaluation, treatment etc. should see the following two Sections "DIAGNOSTIC RENAL..." and "DNA DIAGNOSTIC SERVICES." Others with known or suspected hereditary kidney disease may initiate participation in the research study writing or calling Dr. Denison. She will collect family and medical information, blood specimens, and possibly arrange for a free research clinic for various family members. If you are unable to attend our clinic, we may ask you to have your blood drawn at your own expense (possibly a tax deduction as a contribution to medical research), and we will pay for its shipment to Utah. Your participation is voluntary and you can expect no compensation, reimbursement, or other benefit except knowing that you are contributing to research that may eventually help your family. When and if we discover the genetic basis of the kidney problem in your family, we will inform you, and you may thence on your own deal with renal clinics and DNA diagnostic laboratories.
Research subjects have often requested that we send reports to insurance companies, employers, schools, etc. We have determined that under law and University of Utah regulations, our research study cannot under any circumstances provide information to third parties. If the research and family studies reveal any problems, we will give you the necessary information to refer yourself to services described below.
DIAGNOSTIC RENAL (NEPHROLOGY OR KIDNEY) CLINICS: These fee-for-service clinics and other standard health-care providers provide diagnoses, evaluations and prognoses, and treatments that you may need. Also, you may request from them any reports desired. Dr. Gregory of our study conducts one such clinic. He may also direct you to other clinics throughout the world, particularly those with experience and genetics capabilities regarding hereditary nephritis.
DNA DIAGNOSTIC SERVICES: Individuals in 20 of the "University of Utah Alport Study kindreds" may right now today! benefit from our research by obtaining the genetic diagnostic services of Dr. Kenneth Ward. You may confirm whether you are a member of these 20 kindreds by calling or writing Dr. Denison.
Genetic testing is relatively expensive. It is, however, covered by many forms of health insurance and -- for the present -- Dr. Ward's operation is subsidized by one of the Eccles Foundations. DNA tests can be used to diagnose "at risk" children that may show few or no signs or symptoms of Alport syndrome. Gene-carrier status may also be determined in asymptomatic adult females at risk, as well as in potential kidney donors within a family. Prenatal DNA testing is also possible.
Because of the complexities of DNA testing it must be arranged through your physician or Dr. Gregory's renal clinic.
On September 18, 1992, Mr. Roger G. Stratford, President of the National Kidney Foundation of Utah (NKFU), announced a research grant of $6,250 for the study "Genetic Characterization of Autosomal Dominant Alport Syndrome." Recipients of this grant are Dr. Curtis L. Atkin of the Biochemistry Department at University of Utah, and his colleagues Dr. David F. Barker and others.
Dr. Atkin said that the majority of families with hereditary nephritis, or Alport syndrome, inherit the kidney disease in an X-linked pattern. In many -- perhaps all -- such cases this pattern of inheritance arises because the genetic misinformation that causes the kidney disease lies in the COL4A5 gene in the Xq22 region of the X chromosome. The COL4A5 gene determines the structure of the protein alpha5(IV) collagen, which protein has a major role in the glomeruli (filtration units) of kidneys. The University of Utah research group, particularly Dr. Barker, and Dr. Karl Tryggvason and Dr. Jing Zhou at University of Oulu, Finland, identified mutations of the COL4A5 gene as the fundamental causes of X-linked Alport syndrome.
A minority of families with Alport syndrome, however, show a different pattern called autosomal dominant inheritance. Drs. Atkin and Barker say that this different pattern means that the disease is caused by abnormal information in an unknown gene or genes lying somewhere among the 22 autosome chromosomes. Four families of 78 under study at University of Utah seem to have autosomal dominant inheritance. The new research supported by NKFU is aimed at finding the responsible gene(s) for autosomal dominant Alport syndrome. Drs. Atkin and Barker say that locating the gene(s) is the crucial first step to determining the molecular abnormalities of the gene(s) and protein(s) involved.
The National Kidney Foundation of Utah is pleased to announce the award of two Research Grants, each of $6,250 to promote research into kidney disease. One award has been made to Dr. Mahmoud Loghman-Adham and one to Dr. Curtis L. Atkin.
The award to Dr. Mahmoud Loghman-Adham will assist him in his research into phosphate transport in the kidney. Phosphate is an element that is present in our diet and that is required for normal growth of all parts of the body, but particularly for bones. If the balance of phosphorus in the body becomes too high, a situation familiar to nearly all dialysis patients occurs: painful deposits of phosphate and calcium usually around joints, and the parathyroid glands grow too large, often necessitating their removal by an operation. If there is too little phosphate in a child's body, bones become weak and deformed and the child will develop rickets.
The kidney regulates the amount of phosphate in the body by excreting just the right amount in the urine. This task is performed in a part of the kidney called the proximal renal tubule. Dr. Loghman-Adham has been working on movement of phosphate by the cells of the proximal tubule for many years and has developed a national reputation for his work. This grant will help enable him to continue working on the importance of tight junctions in phosphate transport. Tight junctions are points at which cells in the proximal tubules are held firmly against one another. No one knows how important it is to keep cells tightly cemented to each other, so his work will carry a step further our understanding of the way that the kidney performs the vital task of preserving the right balance of phosphate in the body.
Dr. Curtis Atkin has been working consistently on the inherited kidney condition, Alport Syndrome, for longer than anyone else in the world. Alport Syndrome is a form of nephritis that is often accompanied by hearing loss. It causes kidney failure in boys in their teens or in men in their prime of life. Dr. Atkin's resolute work resulted in proof that Alport Syndrome is inherited as an X-linked condition, one that causes its most severe effects in men and boys, although is inherited through women who are relatively mildly affected or unaffected. His proof of X-linkage laid the groundwork for the identification of the gene responsible for Alport Syndrome and the subsequent discovery of mutations, work to which Dr. Atkin also contributed and for which has been internationally recognized. It turns out that in a few families, Alport Syndrome is not inherited in an X-linked fashion.
The National Kidney Foundation of Utah grant will enable Dr. Atkin to continue searching for the gene responsible for nephritis in these different families. It is important to find the gene for two reasons. Finding the gene is a tremendous step toward eventually finding a cure or really effective treatment for the condition.
Even before a cure is found, finding the gene enables precise diagnoses to be made in some families and will avoid the need for some kidney biopsies. These are enormously worthwhile goals and ones which stand to bring benefits to innumerable people, particularly to the many families with Alport Syndrome in Utah and Idaho.
The National Kidney Foundation of Utah can be justly proud of its support for kidney research in Utah. Every grant helps in the fight against kidney disease, but these two are doubly valuable because they go to support two lines of research that might otherwise have come to a halt because other sources of funding were ending.
It is known that many cases of Alport Syndrome (AS) are caused by a mutation in COL4A5, a gene which produces a component of a specific type of collagen. However, the abnormal DNA sequence within the gene has been identified in only a few families. This may be because the gene is very large and unrelated patients are not expected to have the same abnormality in the gene. It may also be due to current limits in molecular technology which is imperfect but constantly improving. Finally it may be that we have underestimated the number of cases of severe hereditary nephritis that are not caused by abnormalities in COL4A5.
For families where a direct COL4A5 mutation test is not yet possible it may be possible to determine if COL4A5 is responsible for hereditary nephritis by indirect means. This is because DNA sequences that are close to each other on the chromosome tend to be inherited together. Many DNA sequences vary from individual to individual; for example, the DNA that determines eye color or blood type. We have found sequences within COL4A5 that vary widely from individual to individual with no apparent effect on renal function.
In addition to the normal variation we have found within the COL4A5 gene, we have identified and mapped about 20 other variable sequences that are very close to COL4A5 on the X chromosome. These variable sequences are called genetic markers. Genetic markers can be used to determine if hereditary nephritis in a family is or is not caused by COL4A5, or if a particular family member is an Alport Syndrome carrier. This indirect method of testing for COL4A5 Alport Syndrome is called genetic linkage. Genetic linkage studies rely on the principle that within a family, the inheritance of nephritis will almost always be associated with the inheritance of a specific nearby sequence. This association depends on how far away the genetic marker is from COL4A5 on the chromosome. This principle is illustrated by the following figure.
A sequence, called marker A, is within or near to COL4A5. When the DNA sequence is tested in many individuals about half of their X-chromosomes are type 1 and the other half are type 2. The male at the top of the pedigree has Alport Syndrome and is type 1 for marker A. His wife has the type 2 sequence for marker A on both of her X-chromosomes. Their daughter has the type 1 sequence on the X-chromosome that she inherited from her father and a type 2 sequence on the X-chromosome that she inherited from her mother. The X-chromosome from her father also carries the COL4A5 sequence that causes Alport Syndrome.
The diagnosis of the granddaughter is not clear from her urinalysis, but both of her X-chromosomes have the type 2 sequence for marker A. If the marker A sequence lies within the COL4A5 gene, we can be almost certain that she did not inherit the abnormal COL4A5 from her grandfather. If marker A is close by but outside the gene, we are less certain that she and her descendants are at low risk for hereditary nephritis, but for many of our markers the chances are over 95% that she has not inherited the abnormal COL4A5.
The family shown in the figure illustrates the basic principle of prediction by genetic linkage, however we are now finding that the situation for Alport Syndrome is much more complicated. Specifically, we have found families with hereditary nephritis that is "unlinked" to COL4A5, that is, there is no association between the inheritance of hereditary nephritis in the family and the inheritance of a marker DNA sequence within or near the gene. We have also found families where a son has inherited nephritis from his father. In these families, hereditary nephritis could not be caused by a gene on the X-chromosome because males do not inherit an X-chromosome from their father.
This means that we must test for an association between the nephritis and marker sequences within or surrounding COL4A5 in order to be sure that Alport Syndrome is caused by a mutation in COL4A5. In small families, an association between a marker sequence and nephritis could occur by chance. Usually it is necessary to test at least 10 family members to be confident that nephritis is caused by COL4A5 but the number of family members that will need to be tested will vary depending upon the family structure. Our genetic linkage studies are closely tied to the COL4A5 mutation detection studies in that we are able to identify and exclude candidate families for COL4A5 mutation testing. We are currently planning studies that will identify the genes that cause hereditary nephritis in the unlinked families that we have found.
One of the most important implications of our past research is that we are now in a better position to understand why the disabling effects of COL4A5 mutations occur at different ages in different individuals. In particular, it is important for us to be able to understand how the onset of end stage renal disease can be delayed. The help of families with hereditary nephritis has been essential to our past research successes and will be even more important as we begin to apply the new technology to understand how specific genes cause kidney disease in individual patients.
The annual meeting of the Hereditary Nephritis Foundation was held June 11, 1992 in Salt Lake City, Utah. It was reported that the HNF has received over $40,000. in donations since our inception.
Dr. Martin C. Gregory discussed the costs of treatment for ESRD and how much of those costs are not covered by insurance. He explained how, in regards to hereditary nephritis, more complex answers are coming more easily. One example being Dr. David Barker's discovery of three different mutations. It was stated that we must go on because the mutation is being found in a minority of families. There are not enough samples to correlate what does what and why.
Joyce Denison Ph.D., reported that of 75 kindreds involved in hereditary nephritis, only 25 are active. Dr. Denison develops pedigree sketches through clinical research. The clinics include a physical and hearing test along with blood and urine samples and a questionnaire. All information is confidential and cannot be released.
David Barker, Ph.D. and Pamela R. Fain, Ph.D. both gave fascinating talks on their research. Through direct diagnosis, or with genetic markers, there is an odds ratio, or likelihood, of association. There is a different mutation in every unrelated family. In order to make correct inference, they need samples from more family members to compare and determine. Some mutations may not be found if enough family members do not participate.
Ten to 100 times more studies are needed to arrive at results. Researchers in Utah, Finland, France and England are trying to find mutations.
New Officers and Board of Trustees were elected.
Webmaster Curtis L. Atkin, 8/31/99