URI Professor Investigates Deadly + Rare Disease
Monday, September 09, 2013
The tragedy of Stevenson's death drew international attention to the rare, little-known genetic disorder, characterized by physical defects, bone marrow failure, and increased susceptibility to cancer. About 1 in 200,000 children in the United States are born with the disease, and treatment options are extremely limited.
“People are continually being exposed to things that damage our DNA, like sunlight, chemicals, and pollutants,” said Howlett. “We have evolved to have hundreds of proteins whose sole function is to fix damaged DNA. We have multiple specialized DNA repair pathways that function continuously to repair damage accrued during our daily lives.” But according to Howlett, there are a handful of diseases – all of them very rare – that are caused by mutations in DNA repair genes. Fanconi anemia is one of them.
“We know that there are at least 16 genes that, when mutated, result in Fanconi anemia,” said Howlett, who teaches in the URI Department of Cell and Molecular Biology. “These 16 genes encode for proteins that function together in a pathway to fix DNA damage. If you have a mutation in any one of these genes, the protein is defective and the repair pathway is broken.” An inability to fix DNA damage can lead to the accumulation of additional mutations, ultimately leading to cancer, one of the characteristics of Fanconi anemia. “Why Fanconi anemia patients also develop physical defects and bone marrow failure remains a mystery,” he added.
A crucial step
Howlett’s research focuses on two of the Fanconi anemia proteins – identified as FANCD2 and FANCI – that function together and are activated through a process called ubiquitination.
“Ubiquitin is a small protein that is physically attached to other proteins after they are made,” Howlett explained. “It’s a molecular tag that provides instructions about the fate of a protein. In certain cases, ubiquitin can specify protein degradation, while in other cases it can signal that a protein needs to be moved from one place to another in the cell. In the case of FANCD2 and FANCI, ubiquitination targets these proteins to damaged DNA.”
Howlett said that the ubiquitination step is especially important because in 90 percent of Fanconi anemia patients, that step is broken.
“An inability to attach ubiquitin to these proteins must be linked to why these kids get bone marrow failure and cancer,” he said. “We want to learn as much as we can about this step – how it’s regulated, how it works, and how can we fix this step when it’s broken – so we can discover new ways to treat this disease.”
Based on the severity of Logan Stevenson’s disease, Howlett speculates that he may have had mutations in one of the two BRCA genes, which are well known for their involvement in hereditary breast and ovarian cancer.
“Females who inherit one bad BRCA gene – like actress Angelina Jolie – have a greatly increased risk for developing breast and ovarian cancer. If you inherit two bad BRCA genes you get Fanconi anemia,” Howlett said. “The same is true for many Fanconi anemia genes. So while this disease is rare, the genes and proteins involved have major relevance for all of us in the fight against cancer. So it’s really important that we figure out what these proteins do.”
Howlett’s research is funded by the National Institutes of Health, the Department of Defense, and the Leukemia Research Foundation. He attends annual meetings of the Fanconi Anemia Research Fund, where he meets with patients, doctors and other researchers, and always returns re-energized to continue his research.
“Stories like Logan’s are heartbreaking,” he said. “There are a lot of very challenging and important questions that need to be addressed to figure out how to fix this disease.”
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