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Scientists Develop Mouse Model to Enable Study of Rare Genetic Disorder Classical Homocystinuria

November 6, 2018

“We created the model to study a single founder mutation, called p.G307S, which causes a single amino acid substitution in the CBS protein,” Kruger said. “Our mice have been genetically engineered so that they express only human p.G307S CBS, and no longer express the murine CBS gene.”“We created the model to study a single founder mutation, called p.G307S, which causes a single amino acid substitution in the CBS protein,” Kruger said. “Our mice have been genetically engineered so that they express only human p.G307S CBS, and no longer express the murine CBS gene.”PHILADELPHIA (November 6, 2018) — Researchers at Fox Chase Cancer Center have created a mouse model that will make it possible to advance understanding of cystathionine beta synthase (CBS) deficiency, also known as classical homocystinuria. CBS deficiency is a rare recessive genetic disorder that causes the accumulation of the toxic amino acid homocysteine in the blood. The paper, authored by Warren D. Kruger, PhD, a professor at Fox Chase, appears in the Journal of Biological Chemistry.

“We created the model to study a single founder mutation, called p.G307S, which causes a single amino acid substitution in the CBS protein,” Kruger said. “Our mice have been genetically engineered so that they express only human p.G307S CBS, and no longer express the murine CBS gene.”

The mouse model, like human patients, presents with a very severe form of the disease. Because the disease is recessive, both parents would have to contribute a copy of the mutation to their child in order for the child to develop homocystinuria.  

Kruger and his team collaborated with Roland Dunbrack, Jr., PhD, a professor in the Molecular Therapeutics Program at Fox Chase, to use computer based modeling techniques to understand why this mutation is so severe. The computer simulations performed by graduate student Simon Kelow in Dunbrack’s lab demonstrated that the mutation disrupts the configuration of the enzyme active site of CBS. The development of a mouse model for p.G307S CBS may make it possible to develop new treatments for the disease.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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