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The family has a rare, hereditary kidney disorder, called autosomal dominant tubulo-interstitial kidney disease (ADTKD-MUC1). Previous studies had already identified that other mutations in MUC1 were capable of causing this rare kidney disease. A mutation in the MUC1 gene causes a change in the mucin 1 protein, which normally makes sure that the kidneys function properly. Due to this change, the mucin 1 protein accumulates, resulting in kidney damage, and ultimately in kidney failure.
By means of a sophisticated technique, whole exome sequencing, the researchers discovered a new abnormality in the family’s MUC1 (mucin 1) gene. This technique enables researchers to screen a large number of genes simultaneously for the presence of mutations. In this family, the affected members turned out to have a novel abnormality in the MUC1 gene, which healthy members did not. Abnormalities in MUC1 are usually extremely difficult to detect with whole exome sequencing or other sophisticated genetic techniques. This is due to the structure of the MUC1 gene, which comprises a large number of repeats of certain parts of the genetic code, as a result of which a single abnormality in this repeat area will easily stay under the radar. This particular abnormality coincidentally happened to be found just before this area of repeats, so that it could actually be picked up.
The family concerned is very large, with more than 350 family members from eight generations. Not all family members have this kidney disease. Martin de Borst: “In the past few decades, we have treated several family members with either dialysis or a kidney transplant. We had a hunch that it had to be a hereditary kidney disease, but which disease exactly was a mystery up till now.” The research into the cause of the disease was preceded by a detailed genealogical study. The researchers were able to contact family members who were ill and already known at the hospitals directly. These family members subsequently asked other family members who were healthy to also participate in this research.
According to Dr De Borst, the patients are relieved that they now finally know what disease they are exactly suffering from and also what causes it. “We will continue to conduct our research in this family. Some of the members developed kidney failure already at a very young age, whereas other ones only contracted the disease much later. Perhaps the difference can be explained by other genetic factors, or by differences in lifestyle. That we don’t know yet.”
At the moment, there is no treatment for this rare kidney disease. Research into new treatments, such as gene therapy, with which it would be possible to repair the defective MUC1 gene, is well under way. A better understanding of the ADTKD kidney disease, gained from further research conducted among these family members, may lead to new treatment options in due time.
In one of five patients suffering from kidney failure, the underlying cause remains unclear. Recent developments in genetic techniques, however, have made it possible to make a diagnosis more often. According to Dr De Borst, this is not only important for more effective treatment of patients: “It also helps us to advise and support patients and their families more efficiently, for instance, with regard to questions about pregnancy or suitability as a kidney donor.”
The research that led to this extraordinary finding was conducted by a team of nephrologists and clinical geneticists from the UMCG and the UMC Utrecht. The diagnosis was confirmed in cooperation with researchers and genetics specialists in the Czech Republic and the United States.
The findings were published today in the international scientific journal Kidney International. The research was partly funded by Health Holland.
In the Netherlands, about 10% of the population suffers from chronic kidney disease (CKD). More than 18,000 patients have developed kidney failure, requiring dialysis or a functioning kidney transplant to stay alive. In the coming years, CKD will be among the fastest rising causes of death, and is anticipated to be the fifth leading cause of death by the year 2040. This alarming development is fuelled by the ageing population and the increasing numbers of individuals with diabetes and hypertension.