Gene mutation discovered in blood disorder

Sept. 24, 2014

An international team of scientists has identified a gene 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.

The study, co-led by Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia (CHOP), was published recently in the journal Blood. Hakonarson and CHOP colleagues collaborated with Australian scientists.

The research team studied an Australian family with aplastic anemia and other blood disorders, including leukemia. It performed whole-exome sequencing on DNA from the families and identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.

Telomeres, structures made of DNA and protein, are located on the end of chromosomes, where they protect the chromosomes’ stability. They are sometimes compared to aglets, the plastic tips at the end of shoelaces that prevent the laces from fraying. 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. Certain inherited and acquired disorders may also 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 researchers 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. They 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. Read the study abstract.

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