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Nov 26 2014

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International Team Finds Blood Disorder Mutation

blood disorderAn international team of gene experts has identified a mutation that causes aplastic anemia, a serious blood disorder in which the bone marrow fails to produce normal amounts of blood cells. Studying a family in which three generations had blood disorders, the researchers discovered a defect in a gene that regulates telomeres, chromosomal structures with crucial roles in normal cell function.

“Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production,” said the study’s co-leader, Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia. Dr. Hakonarson and a number of other CHOP investigators collaborated with Australian scientists on the study, what was published in the journal Blood.

The research team studied an Australian family with aplastic anemia and other blood disorders, including leukemia. The investigators identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.Complex structures made of DNA and protein, telomeres are located on the end of chromosomes, where they protect the chromosomes’ stability. They are sometimes compared to shoelaces’ plastic tips.

Telomeres shorten after each cell division, and gradually lose their protective function. Aging cells, with their shortened telomeres, become progressively more vulnerable to DNA damage and cell death. Separately from the aging process, certain inherited and acquired disorders may shorten telomeres and injure rapidly dividing blood-forming cells produced in bone marrow. This leads to bone marrow failure, one example of which is aplastic anemia.

The Australian team investigated the function of the ACD gene. They determined that the mutation shortened telomeres and interrupted the ability of telomeres to attract the enzyme telomerase, which counteracts telomere shortening and thus protects cells. The researchers showed that the mutation in ACD alters the telomere-binding protein TPP1, disrupting the interactions between telomere and telomerase. Without access to telomerase to help maintain telomeres, blood cells lose their structural integrity and die, resulting in bone marrow failure and aplastic anemia.

“This improved understanding of the underlying molecular mechanisms may suggest new approaches to treating disorders such as aplastic anemia,” said Dr. Hakonarson. “For instance, investigators may identify other avenues for recruiting telomerase to telomeres to restore its protective function.”

To read more about the innovative work being done at the Center for Applied Genomics, see the Center’s website.

Permanent link to this article: http://blog.research.chop.edu/international-team-finds-blood-disorder-mutation/