JAK2 gene

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Essential thrombocythemia

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic mutations in the JAK2 gene are associated with essential thrombocythemia, a disorder characterized by an increased number of platelets, the blood cells involved in normal blood clotting. The most common mutation (written as Val617Phe or V617F) replaces the protein building block (amino acid) valine with the amino acid phenylalanine at position 617 in the protein. This particular mutation is found in approximately half of people with essential thrombocythemia. A small number of affected individuals have a somatic mutation in another part of the JAK2 gene known as exon 12.

The V617F JAK2 gene mutation results in the production of a JAK2 protein that is constantly turned on (constitutively activated), which, in essential thrombocythemia, leads to the overproduction of abnormal blood cells called megakaryocytes. Because platelets are formed from megakaryocytes, the overproduction of megakaryocytes results in an increased number of platelets. Excess platelets can cause abnormal blood clotting (thrombosis), which leads to many signs and symptoms of essential thrombocythemia.

Polycythemia vera

Somatic mutations in the JAK2 gene are associated with polycythemia vera, a disorder characterized by uncontrolled blood cell production. The V617F mutation is found in approximately 96 percent of people with polycythemia vera. About 3 percent of affected individuals have a somatic mutation in the exon 12 region of the JAK2 gene.

JAK2 gene mutations result in the production of a constitutively activated JAK2 protein, which seems to improve the survival of the cell and increase production of blood cells. With so many extra cells in the bloodstream, abnormal blood clots are more likely to form. In addition, the thicker blood flows more slowly throughout the body, which prevents organs from receiving enough oxygen. Many of the signs and symptoms of polycythemia vera are related to a lack of oxygen in body tissues.

Primary myelofibrosis

Somatic JAK2 gene mutations are also associated with primary myelofibrosis, a condition in which bone marrow is replaced by scar tissue (fibrosis). The V617F mutation is found in approximately half of individuals with primary myelofibrosis. A small number of people with this condition have mutations in the exon 12 region of the gene. These JAK2 gene mutations result in a constitutively active JAK2 protein, which leads to the overproduction of abnormal megakaryocytes. These megakaryocytes stimulate other cells to release collagen, a protein that normally provides structural support for the cells in the bone marrow but causes scar tissue formation in primary myelofibrosis. Because of the fibrosis, the bone marrow cannot produce enough normal blood cells, leading to the signs and symptoms of the condition.

Other disorders

Somatic JAK2 gene mutations are also associated with several related conditions. The V617F mutation is occasionally found in people with cancer of blood-forming cells (leukemia) or other bone marrow disorders. Budd-Chiari syndrome, which results from a blocked vein in the liver, can also be associated with the V617F mutation when it is caused by an underlying bone marrow disorder. It is unknown how one particular mutation can be associated with several conditions.