Call it a quirk or scientific medical miracle. A girl who grew up with a serious genetic immune disease was apparently healed in her 30s by one of its chromosomes breaking apart and reassembling. Scientists traced the improvement of woman removing a deleterious gene by the interference of DNA in one of its cells-a phenomenon recently identified strains of blood that until now had only been linked to cancer .
The woman, who lives in Cincinnati, Ohio, suffered from recurrent bacterial infections as a child. At the time, the doctors found that she had an abnormally low level of white blood cells needed to fight against invading microbes. 9 years of the disease, described in two reports in 1964 The New England Journal of Medicine , was the first known case of what is now called WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. In this extremely rare disease only about 60 cases are known around the world-patients live into adulthood, but they can develop lung damage, hearing loss, and other health problems frequent infections. Those WHIM are also very sensitive to the human papillomavirus, which causes warts on the skin and genital areas that sometimes become cancerous.
In 03, researchers WHIM linked to a gene called CXCR4 , which encodes a cell surface protein that immune cells use to recognize chemical messengers called chemokines. In WHIM, patients have a normal copy CXCR4 and a defective copy that causes the receptor to be overactive he does not cut when it is supposed to. This causes a sort of white blood cells to "get stuck" in the bone marrow instead of entering the bloodstream, said Philip Murphy, an immunologist at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.
Murphy and his colleagues studied the WHIM patients at the National Institutes of Health (NIH) Health Clinical Center to better understand the disease and develop a possible treatment with a drug that inhibits CXCR4 . There are two years, they heard a woman who said she wanted to bring in his two daughters for evaluation because they had inherited the disease.
The woman was the first patient WHIM, now 59 years old. Her two daughters in their early 20s have indeed had classic symptoms of WHIM, like warts on the hands, and blood cells carried the mutation in CXCR4 which usually causes. But their mother, "When we asked a very simple question-'How she doing?" - She said she was fine, "Murphy recalls She did not have warts or severe infections since. his late 30s. "at this point, we were very, very concerned," he said.
the NIH team began sleuthing. to his surprise, the white blood cells of women had more failure CXCR4 mutation, although other types of cells made yet examination of chromosomes in its apparently normal white blood cells, they found an anomaly. a copy of chromosome 2 was about 15% shorter than the other copy. the whole genome sequencing has revealed that he became confused and lost a piece that included failure CXCR4 and 163 other normal genes.
The explanation seems to be chromothripsis, a phenomenon discovered only four years ago a leukemia patient and sometimes observed in other cancers. A chromosome is broken in some way during cell replication, and then reassembles the pieces in a different order. Presumably the cells usually die because of this damage, said Murphy. If the cell survives, scrambled genes can contribute to cancer.
In this case, however, the bursting of the chromosomes appears to have occurred in a blood stem cell, which then replicated to give him a power of normal white blood cells. The missing copy CXCR4 also seems to explain why the cells are now all its white blood cells, say researchers from the NIH. They have shown that stem cell lacking a copy of CXCR4 engraft better in mice that stem cells with two normal copies or a normal copy and WHIM version they report online today in cell .
Murphy said the case of the woman shows that chromothripsis can be curative, and it is useful to check for it in patients with other rare diseases that get better spontaneously. It also suggests that disabling a copy of CXCR4 could improve efforts to treat diseases such as sickle cell anemia by modifying a genetic defect in the stem cells of the blood and the return of patient's cells. Deleting a copy of CXCR4 for the repair of broken gene could transplant graft more easily, said Murphy.
"Very interesting," says clinical geneticist George Diaz of Medicine Mount Sinai Icahn School in New York, who identified CXCR4 mutations as the cause of WHIM. He said the restoration of the woman reminds him of the history of the Berlin patient, an HIV-positive man who developed leukemia and became virus after receiving a bone marrow transplant from a donor lacks a chemokine receptor that HIV needs to enter cells. Improving engraftment in mice lacking a copy of CXCR4 , Diaz added, "certainly could have clinical applications downstream."
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