Surendran Lab Is Assessing Mutations, Kidney Diseases, and Disease Variability in Alagille Syndrome
Kameswaran Surendran, PhD, Associate Professor of Basic Biomedical Sciences at the University of South Dakota, and colleagues in the Surendran Lab assess the cellular and genetic basis of kidney diseases associated with Alagille Syndrome. Here he talks about what his lab is working on in Alagille syndrome.
Question:
Can you describe the research the Surendran lab is doing on the cellular and genetic basis of kidney diseases associated with Alagille syndrome?
Kameswaran Sunendran, PhD:
Alagille syndrome has been associated with mutations in a gene called JAGGED1 and another gene called NOTCH2. What’s interesting though is that not everyone who has a mutation in these genes—JAGGED1, NOTCH2—actually go on to develop kidney disease. In fact, it happens in roughly 40% of those with mutations in JAGGED1.
One of our interests in the Surendran lab is to understand what is Notch doing in the kidney during development and can we better understand why there is this variability in disease? Are there additional genetic mutations that perhaps might explain why some people go on to get kidney disease, whereas others don’t? We’re actually modeling different NOTCH2 mutations that have been identified in people, and we’re modeling these in cell lines and in mice to test one hypothesis. One of the hypotheses is that it’s only certain mutations in the NOTCH2 that will result in kidney disease, whereas others will not. We’re modeling that to test that.
An alternative hypothesis is that it’s not just simply a mutation in JAGGED1 or NOTCH2, that there might be other mutations within the Notch pathway and perhaps that’s important in whether or not someone will on to develop kidney disease. We’re testing that second hypothesis by performing whole exome sequencing of samples that we obtain from people diagnosed with Alagille syndrome and their family members.
Another aspect that is really at the heart of what we are trying to do is understand the function of Notch in kidney epithelial cells. For this we are looking at the cellular processes that are altered when the NOTCH2 is mutated. We model the exact mutation that happens in Alagille syndrome and see what are the cellular processes that are altered. We are also looking at what are the proteins that the NOTCH2 normally sees within the kidney epithelium. This is a way for us to try to understand what are the proteins mediate the function of Notch. We’ve generated a list of proteins that the NOTCH2 normally sees. What we’re currently doing is trying to determine which of those do the mutant NOTCH2 proteins not see anymore. Because they don’t see it, that might be important. It might be an important clue as to how the kidney abnormality occurs.
One final thing that we are doing in the lab is based on the knowledge that we’re gaining; we are testing various ways of rescuing the kidney abnormalities. For instance, we have identified that the kidney cells have longer antenna-like structures when the Notch is mutated, and we’re trying to test the hypothesis, can we somehow reduce that cilia length and will that actually improve or slow down the kidney disease progression in mice?
Those are the kind of things that we’re doing in the lab to better understand the kidney disease associated with Alagille syndrome.
Question:
Has your research team determined whether there is a genetic explanation for the disease variability in Alagille syndrome?
Kameswaran Sunendran, PhD:
The short answer is no, we haven’t yet. But as I mentioned, one of our hypothesis is that apart from mutations in JAGGED1 and NOTCH2, there may be other additional mutations. We’re in the process of testing this. The reason we think this may be true is that in our mouse studies we definitely see examples of that where if we have mutations in, apart from NOTCH2, if we also mutate NOTCH1, the kidney disease becomes a lot more severe and it occurs more consistently.
In the human studies, we’re at the very early stages. We’ve done some whole exome sequencing, and we are finding examples where there are people with mutations in JAGGED1 who also have additional rare genetic changes in Notch pathway genes, and currently there’s a correlation that those people may go on to develop kidney disease, but we are actively testing that in the cell lines and in mice to actually confirm whether that is really true. That’s where we’re at with that.
Question:
How has identifying the mutations in Alagille syndrome impacted this space?
Kameswaran Sunendran, PhD:
I think that the JAGGED1 and the NOTCH2 genes are associated with Alagille syndrome has really changed.
One, it has helped researchers like myself better understand the basis of Alagille syndrome because there’s a lot of knowledge that’s there about Notch signaling that comes from studies from many researchers who have studied the pathway in even lower organisms like fruit fly and so on. How this pathway works, there’s a lot that’s known. One can potentially tap into that knowledge and that’s kind of beneficial for researchers in trying to understand what goes wrong in Alagille syndrome.
The other aspect, although I’m not a clinician, I think it’s definitely helped clinicians to diagnose who has Alagille syndrome, especially considering the variability of the disease. It sometimes becomes hard to say who has Alagille syndrome or who doesn’t. By testing whether someone has a mutation in JAGGED1 or NOTCH2, it can become a little bit more easier to diagnose whether they have Alagille syndrome or not.
Rare Disease 360® is the Official Media Partner and Official Publication of The Alagille Syndrome Alliance (Alagille.org).
