of women in a family
By studying 3 generations of a family plagued by blood disorders, researchers discovered a genetic mutation that causes aplastic anemia.
The team 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.
The mutation disrupts the interactions between telomeres and telomerase, which causes blood cells to die and results in aplastic anemia.
“Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production,” said Hakon Hakonarson, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.
Dr Hakonarson and his colleagues described this research in Blood.
The team studied an Australian family with aplastic anemia and other hematopoietic disorders, including leukemia. Whole-exome sequencing of the family’s DNA revealed an inherited mutation on the ACD gene.
The mutation is an amino acid deletion in the TEL patch of TPP1 (ΔK170). All of the family members with this mutation had short telomeres, and those with wild-type TPP1 did not.
The researchers introduced TPP1 with the ΔK170 mutation into 293T cells and found the protein could localize to telomeres but failed to recruit telomerase. The team said this indicates a causal relationship between the mutation and bone marrow disorders.
Without access to telomerase to help maintain telomeres, blood cells lose their structural integrity and die, resulting in bone marrow failure and aplastic anemia.
Nine other genes were previously found to play a role in bone marrow failure disorders. The current study adds ACD to the list and is the first time the gene has been shown to have a disease-causing role.
“This improved understanding of the underlying molecular mechanisms may suggest new approaches to treating disorders such as aplastic anemia,” Dr Hakonarson said. “For instance, investigators may identify other avenues for recruiting telomerase to telomeres to restore its protective function.”
