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The diabetes gene that broke all the rules

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For more than a decade, the Bashir family had no idea why their daughter Tania was born without a pancreas. Now, after years of testing, genomics researchers finally found the cause: a mutation in a gene only found in primates. The finding gives diabetes researchers new insight into how the pancreas develops and hope for new treatments for people with type 1 diabetes and neonatal diabetes.

Host: Stephanie DeMarco, PhD, Associate Editor, Team Lead

Guests:

Imran Bashir

Andrew Hattersley,

Andrew Hattersley, University of Exeter

Elisa De Franco

Elisa De Franco, University of Exeter  

Lori Sussel

Lori Sussel, University of Colorado Anschutz

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Transcript

Stephanie DeMarco: Hello everyone! Welcome back to a new episode of DDN Dialogues! I’m your host, Stephanie DeMarco. 

Today’s episode is about a genetic mystery that has been more than ten years in the making. We’ll get into the surprisingly complex biology of the pancreas as well as a new genomic finding that changes how researchers think about how the pancreas develops.

But before we get into all of that, we need to go back to the beginning. Our story starts with the Bashir family, in particular Imran Bashir.

Imran Bashir: I have five daughters. It was not the plan to have such a big family. I think the plan was one boy one girl, and we had a girl, try for a boy; had another girl, tried for a boy; and had a third, and then stopped and said, yep, that’s alright! God gave me a sign, and that’s enough. And then I was away from home, and my wife texted me, and she says, “I’m pregnant,” which is certainly a surprise, and then a second text message about thirty seconds later saying, “It’s twins!” It was certainly a surprise! Came home, and we just both looked at each other, and said, what do we do now? But, we always believed that things happen for a reason.

About halfway through the pregnancy, they had a routine scan. They realized that one of the twins was a lot smaller than the other, and from then on in, it was weekly scans. In the end, there was a real risk to one of the twins, so they induced early. And the girls were born. I was told before they were born that it’s going to be five weeks in hospital. Nine months later, Tania was still in hospital.

They found out fairly early that she was diabetic. And then I started learning about diabetes and neonatal diabetes especially, and reading stuff about it being temporary, and they can grow out of it and things like that. The problem that we saw as parents was that she wasn’t putting on any weight, and then her stools were really really runny. So because of that, they started doing more and more tests, and then they realized through an ultrasound that she doesn’t actually have a pancreas at all. And that’s when everything went, I’d say, through the looking glass.

DeMarco: Unlike the more common type 1 or type 2 diabetes, neonatal diabetes is rare. It’s caused by single mutations in genes that the body needs to make insulin. But, because insulin is the end product of a series of different biological processes in the body, there are lots of different ways for insulin production to go wrong. Andrew Hattersley, a University of Exeter researcher who has studied neonatal diabetes since 1992, told me more.

Andrew Hattersley: If you’ve got no insulin when you’re born, there are three possibilities. One is that you’ve got beta cells, and they’re not working. The other possibility is you have got beta cells, but they’re being destroyed, either by the immune system or by ER stress. And the third one was this group of development of the beta cell. 

DeMarco: If someone has a mutation in a gene that affects beta cell development, their body may not make beta cells. Or, if they have mutation in a gene that’s needed very early in pancreas development, their body might not make a pancreas at all. By figuring out which genes are mutated in kids with neonatal diabetes, Hattersley and his colleagues hope to understand the disease better and find new ways to treat it. To do that, Hattersley cofounded the genetic testing service at Exeter University called Diabetes Genes. Hattersley and his team have collected and sequenced DNA samples from more than 3,000 patients with neonatal diabetes from 113 different countries as of July 2023. 

One of those patients was Tania.

When the Bashir family sent the Exeter team her DNA sample, they figured that they’d soon have an answer for why Tania was born without a pancreas. But when the results came back, the tests were negative. Tania had none of the standard mutations known to cause neonatal diabetes. 

Bashir: Exeter contacted us and said, “We want to set up a family day for people from around the world like Tania and would you be willing to come along to that, because not only would we want to meet them, we want to actually take samples, so we could do further testing, and samples of family members as well.” So I spoke to my wife, and it’s something we’d absolutely wanted to do.

What we realized quite early on was that a lot of other families that were like Tania had an answer. One of the mutations is called GATA6, and a lot of them knew that they had a GATA6  mutation. And I was like, but why doesn’t Tania have that?

DeMarco: Neonatal diabetes is rare, but the subset of kids who have the disease because they are born without a pancreas like Tania, are even rarer.

Hattersley: In total, we found about 110 patients born without a pancreas.

DeMarco: As the years went by, the Bashir family waited for an answer. At one point, they went to meet the researchers at the lab in Exeter, including Elisa De Franco, who is now the scientific lead of the genetic testing service. 

Elisa De Franco: I do remember when Imran and his wife and Tania came over to visit the lab. At the time, I was a PhD student sequencing all of these genes. And meeting the family kind of really brings it home like how much it means to them, so I really wanted to find an answer for them.

DeMarco: While very few people are born without a pancreas, genetic studies of these individuals have identified a few important genes. The most common mutation falls in the GATA genes, which encode transcription factors. A mutation in just one copy of GATA6, for example, is enough to prevent pancreas development. The same is true if there is a mutation in the related gene GATA4. Hattersley, De Franco, and their colleagues also identified a handful of other genes mutated in people without pancreases. 

De Franco: Some of the genes that we found were genes where a heterozygous mutation was causing no pancreas in humans, but actually a mouse that had exactly the same mutation was living happily with no sign of diabetes whatsoever. And actually, the whole gene needed to be knocked out in both copies to be able to start seeing an effect. So there was some hints there that actually studying the genetics of these kids could give us insights that we couldn’t get just from studying mouse models or studying cells.

DeMarco: In addition to Tania, a family from Saudi Arabia had been referred to the genetic sequencing center at Exeter. They also had a child born without a pancreas who had none of the other mutations known to cause neonatal diabetes. De Franco and her team performed exome sequencing on this child, Tania, and both sets of parents. They found that both kids had mutations in the gene ZNF808.

De Franco: Both of them had mutations which resulted in complete loss of this gene that is found in humans and is found in higher primates, but it’s not present in other mammals at all. So, it’s a gene that is not present in mouse, which was extremely surprising, but also really, really interesting.

The kind of dogma has always been that things that are so important for development of a whole organ like a pancreas, which is essential, then probably have been highly conserved through evolution. So all of the pathways are very likely to be the same. And that’s why studying development in models like mouse has had so much value in the past because we could assume that there were going to be similarities that had been kept the same throughout evolution. 

So initially, when we found that this gene was just present in primates, we thought, oh this is really exciting. We couldn’t find any other example of a congenital developmental disease that was caused by the loss of a gene that was just present in primates, which doesn’t mean that there aren’t any. And actually, I’m sure that more will be discovered now that we have so much power with genetic studies. But I think it was a really good example also for us to kind of start to think actually we shouldn’t look just at things that are conserved through species. What we found was that is something that was quite rare.

DeMarco: As De Franco and her team dug into the biology of ZNF808, they identified eleven other families who had children born without pancreases and who had mutations in this same gene. The researchers found that ZNF808  is a member of the KRAB zinc finger protein family, which is a family of proteins that binds DNA. When the researchers analyzed published chromatin binding data, they saw that these proteins specifically bind to transposable elements called MER11 elements, which are important for regulating gene expression.

Normally, when researchers want to know how a gene functions, they knock it out in an animal model like a mouse, but because ZNF808  isn’t present in mice, the team didn’t have that option. Instead, the researchers turned to stem cells. When they knocked out ZNF808  in human embryonic stem cells, the repressive chromatin marks that had decorated MER11 elements disappeared. In their place, active chromatin marks appeared. They then looked at gene expression of both ZNF808  knockout cells as well as cells taken from patients born without a pancreas. They saw that as the induced pluripotent stem cells developed, rather than genes involved in pancreas development turning on, liver development genes did.

Hattersley: In the end, what we think is it’s a diversion towards the liver, away from the pancreas.

Bashir: For Tania, her immune system hasn’t gone out of its way to attack the cells. It’s just like she’s taken a wrong turn, and therefore can never end up with the pancreas.

DeMarco: The discovery of ZNF808’s role in controlling MER11 elements to steer stems cells’ away from developing into a liver and toward making a pancreas impressed Lori Sussel, who is a pancreas development researcher at the University of Colorado Anschutz who was not involved in this study.

Lori Sussel: This study is showing this whole new mechanism for how pancreas development is regulated in humans. Everyone thinks transposable elements are jumping around, but they’re involved in regulation, which I think is really super novel.

De Franco: Ideally, what we would really like to find out is what specific pathway is being regulated by ZNF808. Is it just some of these transposable elements? Is just one of these transposable elements that is really important for pancreatic development or for liver development? A lot more questions remain to be answered.

Sussel: One thing we don’t know is if ZNF8[08]  actually functions in the adult. At this point, it looks like it’s very important for development. So I think the next step would be to see is it also responsible for maintaining pancreas identity and function in the adults? Because it definitely is expressed in the adults.

It’s also expressed in a lot of different tissues like thyroid, both in the embryo and in the adult, yet it seemed like they had a very specific phenotype. So, it would be interesting to see if there are other phenotypes as maybe these patients age because it seemed like very specific to the pancreas yet, ZNF808  is also expressed in these other tissues.

De Franco: Since we’ve started using genome sequencing, we find quite often that the genetic finding is the start to the story. So, we find the gene that causes neonatal diabetes, but why, and what is it doing? What is it regulating?

Bashir: Exeter, absolutely 100%, without their relentless time and effort and meticulous testing they’ve been doing over years and years and years, I’m really happy that we have what you’d class as an answer. 

DeMarco: While researchers’ understanding of ZNF808  is still in its infancy, Hattersley thinks that this new discovery will play an important role in creating replacement beta cells. These cells would benefit both people like Tania as well as people with type 1 diabetes.

Hattersley: We have millions and millions of people throughout the world with type one diabetes who need beta cells, and whilst there’s been great progress in that direction, it is still a difficult thing to create. When we try and make a beta cell, we push it through the early development quickly so we can get on to the final bits. And I think this is showing that this is a critical step in the human pancreas. It really does say, go back to the early stages of development because that’s where man is differing. And if you’re trying to make a human beta cell, which makes enough insulin for a human, then you really want to be following as closely as you can the human pathway.

De Franco: This finding is highlighting how much more we need to learn about how these beta cells develop in vivo. So, I’m also hoping that this finding is going to help the field in refining those protocols so that they can be really efficient and that we can be a step closer towards being able to have beta cell replacement therapy for people with mutations in ZNF808  as well as other people with diabetes.

Hattersley: One thing I would like to really emphasize is how much Tania and her family helped with this research. They were critical in the early stages. They did a skin biopsy, which we were then able to use in the experiments and really established this key thing. And the perfect dream would be that at some time in the future, there is cell therapy available and Tania can have it, and then the cycle will have been completed.

Bashir: Diabetes is something that affects a lot of people across the world. And if this can help their understanding of the pancreas, how it develops in the early years, and what effect it might have on type one diabetics, especially, I think that’d be wonderful.

DeMarco: That’s it for this episode of DDN Dialogues. I’d like to thank Imran Bashir for talking with me about his daughter, Tania. I’d also like to thank Andrew Hattersley, Elisa De Franco, and Lori Sussel for speaking with me as well. And thanks to all of you for listening! Until next time, I’m your host Stephanie DeMarco.

This episode of DDN Dialogues was reported, written, and produced by me with additional audio editing by Jessica Smart. To never miss an episode, subscribe to DDN Dialogues wherever you get your podcasts. And if you like the show, please rate us five stars and leave a review on your favorite podcasting platform. If you’d like to get in touch, you can send me an email at sdemarco@drugdiscoverynews.com.

Thank you again to the Bashir family for allowing me to share your story. And I hope that this episode reminds all of you that a discovery that breaks all the rules may one day lead to new treatments for kids like Tania. 

Correction: February 28, 2024: An earlier version of the story misspelled Tania Bashir’s name. The text has been corrected.

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