multiple hereditary exostoses (MHE) Archives - Sanford Burnham Prebys

Tag: multiple hereditary exostoses (MHE)

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This enzyme is one of the hardest working proteins in the body

AuthorMiles Martin
Date

October 21, 2021

Rendering of a red-orange protein molecule on a black background

Researchers from Sanford Burnham Prebys have shown that a protein they identified plays a major role in the breakdown of hyaluronic acid, a compound found in the scaffolding between our cells. The findings, published recently in the Journal of Biological Chemistry, could have implications for epilepsy, cancer and other human diseases associated with hyaluronic acid and similar compounds.

They also shed light on one of the most active biochemical processes in the body. 

“Our body turns over hyaluronic acid at an extremely rapid rate, far faster than the other compounds surrounding our cells,” says senior author Yu Yamaguchi, MD, PhD, a professor in the Human Genetics Program at Sanford Burnham Prebys.

Hyaluronic acid, a common ingredient in cosmetic anti-aging products, is a one of several large sugar molecules known as glycosaminoglycans (GAGs). These are found naturally in the extracellular matrix, the complex network of organic compounds surrounding our cells that gives structure to our tissues. In addition to its structural role, the extracellular matrix is involved in regulating the immune system and is critical in the early development of connective tissues like cartilage, bone and skin.

“The extracellular matrix is found in every organ and tissue of the body, and malfunctions in its biochemistry can trigger or contribute to a variety of diseases, some of which we don’t even know about yet,” says Yamaguchi. His team studies how GAGs affect childhood diseases including congenital deafness, epilepsy and multiple hereditary exostoses, a rare genetic disorder that causes debilitating cartilage growths on the skeleton.

Hyaluronic acid is also known to be correlated with several health conditions, depending on its concentration in certain tissues. Reduced levels of hyaluronic acid in the skin caused by aging contribute to loss of skin elasticity and reduced capacity to heal without scarring. Levels of hyaluronic acid in the blood dramatically increase in alcoholic liver disease, fatty liver and liver fibrosis. In addition, hyaluronic acid levels have been correlated with increased tumor growth in certain cancers.

“These compounds are literally everywhere in the body, and we continue to learn about how GAG’s influence disease, but there’s also a lot we still don’t know about how these molecules are processed,” says Yamaguchi, “Research like this is about understanding what’s happening at the molecular level so we can later translate that into treatments for disease.” 

For this study, the team focused on a protein called TMEM2, which they had previously found to break down hyaluronic acid by cutting the longer molecule into manageable pieces for other enzymes to process further. Using mice as a research model, they selectively shut off the gene that codes for TMEM2 and were able to successfully measure precisely how much the absence of TMEM2 affects the overall levels of hyaluronic acid.

The answer: a lot.

“We saw up to a 40-fold increase in the amount of hyaluronic acid in the study mice compared to our controls,” says Yamaguchi. “This tells us that TMEM2 is one of the key players in the process of degrading this compound, and its dysfunction may be a key player in driving human diseases.” 

The team further confirmed this role of the TMEM2 protein by using fluorescent compounds that detect hyaluronic acid to determine where the TMEM2 protein is most active. They found the most activity on the surface of cells lining blood vessels in the liver and lymph nodes, which are known to be the main sites of hyaluronic acid degradation. 

“These findings refine our understanding of this critical biochemical process and set us up to explore it further in the interest of developing treatments for human diseases,” says Yamaguchi. “Hyaluronic acid is so much a part of our tissues that there could be any number of diseases out there waiting to benefit from discoveries like these.”

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Autism researcher raising a son with autism shares his story

AuthorMonica May
Date

April 15, 2019

Fumitoshi Irie and his son at a baseball game

Twenty years ago, Fumitoshi Irie, PhD, was conducting his postdoctoral research in Tokyo when he noticed his nearly 2-year-old son, Koji, exhibiting unusual behaviors. 

He didn’t talk often, and when he did, it was garbled. He didn’t make eye contact. He performed repetitive motions. As a neuroscientist, Irie’s instincts sent him to the neurology textbooks at the library. There, he found the symptoms aligned perfectly with autism.  

“Our pediatrician confirmed my suspicions. But at the time, autism was not well known in Japan. A diagnostic system didn’t exist yet, and neither did therapy or other services,” says Irie, now a research assistant professor at Sanford Burnham Prebys in the laboratory of Yu Yamaguchi, MD, PhD “Our doctor told us that the best resources for our son were in the U.S.”

Luckily, moving to America was a natural next step for Irie’s scientific career. He and his wife decided to move to California to join Yamaguchi’s laboratory. He’s worked at Sanford Burnham Prebys ever since. 

“Now, we have great providers and are very happy about the services in San Diego. But I will admit those first years were stressful,” recounts Irie. “Everything changed. We didn’t speak English very well and we didn’t know the right people to contact. It took us a few years to get settled.” 

Autism, also known as autism spectrum disorder (ASD), is a developmental disorder that affects communication and behavior. Symptoms can range from very mild to severe. Approximately 1 in 59 children are diagnosed with autism, according to the Centers for Disease Control and Prevention (CDC), with boys four times more likely to be diagnosed than girls. While the cause of autism is currently unknown, some studies indicate that genetics are involved. However, more research is needed to form a conclusive answer. 

“It’s unlikely that a single gene mutation causes autism,” says Irie. “Multiple factors are likely involved, which explains why the condition appears as a spectrum disorder.” 

A mother’s call sparks new research    

Irie’s autism research originated from an unexpected place: a phone call from a woman named Sarah Ziegler whose son has a rare disease called multiple hereditary exostoses (MHE) that causes numerous bone tumors in children. As the co-founder of the MHE Research Foundation, she noticed that children with MHE often displayed autistic behaviors. 

Irie and Yamaguchi were studying the genes that cause the rare disease, EXT1 and EXT2. These genes are necessary to produce heparan sulfate, a long sugar “tree” that dangles off of the edge of cells and clasps important proteins and molecules. After Sarah’s observation, they began looking into potential connections to autism. 

For Irie, it was a welcome opportunity to study the condition that had changed his life.

First, he created a mouse model that allowed control over the timing and location of EXT1 expression, called a conditional knock out mouse. When he applied a “social reunion test,” in which mice are separated and their behavior post-reunion is studied, he found the reunited mice that lacked EXT1 didn’t interact with each other normally. They co-existed peacefully but didn’t sniff each other and cuddle as they did before. This finding was published in a 2014 paper in the Proceedings of the National Academic of Sciences (PNAS).

Now, Irie is unraveling the molecular dynamics behind this behavior. He’s focused on determining which molecules and proteins interact with heparan sulfate, with a particular focus on the molecular messages sent between neurons. 

Hope for new insights

Irie is quick to note there are caveats to his research: Autism is a spectrum disorder so this may not apply to all children, and heparan sulfate is expressed on many cells and regulates many functions so it is unlikely to be a good target for a potential medicine. 

However, he hopes his research could reveal new insights into autism. While heparan sulfate may not be the right medicinal target, it’s possible there is a protein or still-unknown-factor that interacts with the heparan sulfate “tree” and could be the clue that leads to a drug candidate.  

Today, Irie’s son is almost 22 years old. He lives at home and enjoys participating in a job training program that is organized by the San Diego School District. 

“I love my son just the way he is,” Irie says. “At the same time, I welcome approaches that could ease his suffering because of hypersensitivity or anxiety. Often, everyday experiences are painful to him, such as the sound of a door closing, and it would be wonderful to make that easier for him to bear.”  

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Families find hope at our 10th Annual Rare Disease Day Symposium

AuthorMonica May
Date

March 25, 2019

Rare Disease Day 2019-Sanford Burnham Prebys

The unofficial theme of Sanford Burnham Prebys’ 10th annual Rare Disease Day symposium can be summarized in one word: hope. 

This year’s event focused on rare bone disorders and bone cancers, with a special emphasis on a condition called multiple hereditary exostoses (MHE) that causes numerous bone tumors in children. Until now, children with MHE had only one treatment option: repeated surgeries to remove these tumors. 

Now, the first medicine, called palovarotene, that may be able to slow or halt this bone growth is being tested in a clinical trial—potentially saving these children from a lifetime of painful surgeries. Yu Yamaguchi, MD, PhD, symposium chair and professor in Sanford Burnham Prebys’ Human Genetics program, participated in the key research needed in order for the clinical trial to begin.

“For the first time, a diagnosis doesn’t feel like a life sentence,” says Greta Falkner, who attended the symposium with her 8-year-old son, Jackson Falkner. Jackson has MHE and has undergone 13 surgeries to date. “Today we have hope for a cure.”

The launch of a study evaluating palovarotene as an MHE treatment is the result of decades of hard work and collaboration between scientists, clinicians, Clementia Pharmaceuticals (now Ipsen) and the MHE Research Foundation—a patient advocacy and support group. 

The symposium featured an all-star lineup of distinguished speakers in the field of skeletal biology and MHE research, including keynote speaker Henry Kronenberg, MD, of Massachusetts General Hospital and Maurizio Pacifici, PhD, of Children’s Hospital of Philadelphia, whose research formed the scientific rationale for the use of the drug in MHE. The event was sponsored by the MHE Research Foundation and Clementia Pharmaceuticals. 

“We are so grateful that Sanford Burnham Prebys holds this Rare Disease Day symposium to bring together all the important players in rare disease drug discovery: scientists, doctors, families and drug companies. It is literally ‘bench to bedside’ at one event,” says Sarah Ziegler, who co-founded the MHE Research Foundation with Craig and Susan Eaton after Sarah’s son was diagnosed with MHE in 1993 (when little to no information was available on the disease). “Foundations like ours rely on the research of scientists like Drs. Yamaguchi and Pacifici to find new medicines for patients—and the arrival of the first potential treatment for MHE is the perfect example of the power of this research.” 

Multiple parents and children with MHE, some of whom are enrolled in the clinical trial, attended the event. For most of these children, this was the first time they’d met another person with their condition. 
 

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