Essential thrombocythemia

Several mutations in the MPL gene have been associated with a small number of cases of essential thrombocythemia, a condition characterized by an increased number of platelets in the blood. Platelets are the blood cells involved in blood clotting, and abnormal clotting (thrombosis) is common in people with essential thrombocythemia.

MPL gene mutations associated with essential thrombocythemia change a single protein building block (amino acid) in the thrombopoietin receptor protein. An inherited form of the condition, called familial essential thrombocythemia, is caused by an MPL gene mutation that results in the replacement of the amino acid serine with the amino acid asparagine at position 505 in the protein (written as Ser505Asn or S505N). Essential thrombocythemia that does not run in families (sporadic essential thrombocythemia) has been associated with MPL gene mutations that result in the replacement of the amino acid tryptophan at position 515 with another amino acid, most commonly leucine. These mutations are generally referred to as W515 mutations.

Amino acid changes at position 505 or 515 result in a thrombopoietin receptor protein that is constantly turned on (constitutively activated), which, in essential thrombocythemia, leads to the overproduction of abnormal megakaryocytes and an increased number of platelets. Excess platelets can cause thrombosis, which leads to many signs and symptoms of essential thrombocythemia.

Primary myelofibrosis

Several mutations in the MPL gene have been identified in some people with primary myelofibrosis. This condition is characterized by scar tissue (fibrosis) in the bone marrow, the tissue that produces blood cells.

Like essential thrombocythemia, primary myelofibrosis is associated with the MPL gene mutations referred to as W515 mutations. These mutations lead to a constitutively activated thrombopoietin receptor protein, which results in 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.

It is unknown how the same gene mutations can be associated with different conditions.

Other disorders

Mutations in the MPL gene cause a rare condition called congenital amegakaryocytic thrombocytopenia (CAMT). This condition begins in infancy and is characterized by low numbers of megakaryocytes (megakaryocytopenia) and platelets (thrombocytopenia). CAMT can lead to an impairment of bone marrow function known as bone marrow failure.

The MPL gene mutations involved in CAMT lead to a reduced functioning or nonfunctioning thrombopoietin receptor protein. People with no thrombopoietin receptor function have a severe form of the condition called CAMT I. People with some remaining thrombopoietin receptor function have a milder form of the condition called CAMT II.