A specific genetic alteration, the JAK2 exon 12 mutation, is linked to a group of rare blood disorders called myeloproliferative neoplasms (MPNs). This mutation is acquired during a person’s lifetime and is not inherited.
Understanding the JAK2 Gene and Exon 12 Mutation
The JAK2 gene holds instructions for creating a protein that is part of the JAK/STAT pathway, a communication system that controls the production of blood cells from hematopoietic stem cells in the bone marrow. The JAK2 protein acts as a messenger, transmitting signals to regulate cell growth and division.
A mutation in exon 12 of the JAK2 gene causes this signaling protein to become stuck in the “on” position. This leads to a state of constant activation, independent of normal growth signals, resulting in the uncontrolled production of blood cells, most notably red blood cells.
Associated Condition: Polycythemia Vera
The overproduction of blood cells driven by the JAK2 exon 12 mutation is the defining characteristic of a condition called polycythemia vera (PV). PV is a chronic myeloproliferative neoplasm, a type of blood cancer, where the bone marrow produces an excessive number of red blood cells. In some cases, the production of white blood cells and platelets is also increased.
The primary consequence is that the blood becomes thicker and more viscous, flowing less easily through blood vessels. This condition is a primary form of polycythemia, meaning the cause originates within the bone marrow itself. In PV, red blood cell production becomes independent of the hormones that normally stimulate their creation.
Key Symptoms Linked to the Exon 12 Mutation
Many individuals may be asymptomatic, with the condition discovered through routine blood tests. When symptoms appear, they are primarily a result of increased blood volume and viscosity. General constitutional symptoms are common and include fatigue, weakness, shortness of breath, and unexplained weight loss. These are often related to the blood’s reduced ability to deliver oxygen and the increased workload on the heart.
Circulatory and neurological symptoms can arise from poor blood flow in small vessels. Patients may experience:
- Persistent headaches
- Dizziness
- A ringing in the ears (tinnitus)
- Visual disturbances, such as blurred vision or seeing spots
Some patients report a burning pain in the hands or feet, accompanied by reddish or bluish skin. Skin-related issues are also a hallmark of the condition. A distinctive symptom is aquagenic pruritus, severe itching after exposure to warm water. Another common sign is plethora, a ruddy complexion on the face, palms, and earlobes. An enlarged spleen, or splenomegaly, can also occur, leading to fullness or discomfort in the upper left abdomen.
Comparison with the JAK2 V617F Mutation
While the JAK2 exon 12 mutation is a definitive marker for polycythemia vera, it is significantly rarer than the V617F mutation, which is found in approximately 95% of PV cases. Patients with an exon 12 mutation often have what is described as an “isolated erythrocytosis.” This means their condition is characterized by a high red blood cell count, while their white blood cell and platelet counts are often within the normal range. This is a key distinction from V617F-positive PV, where it is more common to see an elevation in all three blood cell lines.
Furthermore, individuals with the exon 12 mutation tend to be diagnosed at a younger age and may present with higher hemoglobin and hematocrit levels at diagnosis. Symptoms like an enlarged spleen and itching, while possible, may be less frequent or severe in the exon 12-mutated group compared to their V617F counterparts.
Diagnostic Pathway for Suspected Cases
The diagnostic process begins when a patient reports symptoms or a routine blood test reveals abnormalities. The first step is a complete blood count (CBC) to measure blood cell levels, with attention paid to elevated hemoglobin and hematocrit values.
If the CBC results are suspicious for PV, molecular testing for JAK2 mutations is the next step. The test for the V617F mutation is performed first. If that test is negative but clinical suspicion remains high, especially with a low serum erythropoietin (Epo) level, specific testing for exon 12 mutations is conducted. The presence of a JAK2 exon 12 mutation is a major diagnostic criterion for PV.