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New Mutation Identified for Rare Genetic Kidney Disease (MCKD1); Mutant Protein Can Be Detected in Urinary Exosomes, Offering Possible Biomarker for Early Detection of Disease

Medullary cystic kidney disease type 1 (MCKD1) is an autosomal dominant tubulointerstitial kidney disease (ADTKD). Recently, mucin 1 (MUC1) was identified as a causal gene MCKD1. However, the identified MUC1 mutation was found to be a single cytosine insertion in a single copy of the GC-rich variable number of tandem repeats (VNTRs), which are very difficult to analyze by next-generation sequencing. Until now, other mutations had not been detected in ADTKD-MUC1, and the mutant MUC1 protein has not been analyzed because of the difficulty of genetically modifying the VNTR sequence. Now, a second mutation in the causal gene has been identified and this advance may enable earlier detection of the disease, perhaps via protein analysis of urinary exosomes. Despite the general rarity of MCKD1, because it is an autosomal dominant disease, once a causative mutation is in a family, many family members can be affected. Current diagnostic methods discover the disease only late in its development. Recently, Osaka University (Japan) researchers studied one family in which 9 of 26 members were positive for MCKD1 and identified the new mutation in the disease-associated mucin 1 (MUC1) gene that may act as an early marker of the disease. “Besides renal failure and genetic testing, there is little we have to identify the disease,” says Associate Professor Jun-Ya Kaimori, a nephrologist at Osaka University Hospital. “There are very few early signs that show illness.” At the point of renal failure, patients are usually left with only extreme and invasive treatment options, such as dialysis or transplantation. “MCKD1 is caused by a single mutation in MUC1 gene discovered in 2013,” he continued. This mutation is located in a region of the gene that includes GC-rich variable number of tandem repeats (VNTRs). This, explains Dr. Kaimori, makes it very difficult to analyze. “The standard technique to analyze is next-generation sequencing. VNTRs have a tertiary structure that makes it very difficult to analyze by next-generation sequencing. Even finding the [first] mutation took immense time and effort,” he said. In his latest research study, Dr. Kaimori and his colleagues used whole-exome sequencing to analyze the MUC1 gene and found a second mutation outside the VNTR. “The mutation was a deletion of just two base pairs, but that was enough to change the protein structure,” he said.

The original MUC1 mutation was found by a collaboration of scientists from U.S. and European institutes. When asked why his group found the mutation but the international collaboration did not, Dr. Kaimori frankly replied, “It was an unexpected discovery.”

Unlike the first mutation, the location of the new mutation allowed the scientists to study the effects of the mutated protein further. Experiments suggested that the mutation disrupts the function of the MUC1 protein and changes its location inside cells. This last observation excited Dr. Kaimori, because it suggested a potential biomarker with which to diagnose patients before renal failure.

“We found patients had high levels of mutant MUC1 in urinary exosomes, but healthy people had normal MUC1 (image) in urinary exosomes. These results suggest we can use urinary exosomes for non-genetic testing to evaluate the risk of MCKD1.”

The new finding was reported online on June 1, 2017 in Nephrology Dialysis Transplantation. The article is titled “Analysis of an ADTKD Family with a Novel Frameshift Mutation in MUC1 Reveals Characteristic Features of Mutant MUC1 Protein. The authors wrote, “This novel frameshift mutation in the MUC1 gene and consequent mutant protein may contribute to the future discovery of the pathophysiology of ADTKD-MUC1. The mutant MUC1 protein in urine exosomes may be used for non-DNA-related diagnosis.

[Press release] [Nephrology Dialysis Transplantation abstract]