Paroxysmal nocturnal hemoglobinuria

Variants (also known as mutations) in the PIGA gene cause a condition called paroxysmal nocturnal hemoglobinuria (PNH). People with this condition have episodes of  blood in the urine (hemoglobinuria) that results from the breakdown of red blood cells. A tendency to develop blood clots (thrombosis) and other blood-cell abnormalities also occur in this condition.

In people with PNH, variants of the PIGA gene occur during a person’s lifetime and are present only in certain cells. These changes, which are called somatic variants, are not inherited. For the condition to develop, one or more somatic PIGA gene variants occur in blood-forming cells called hematopoietic stem cells. Hematopoietic stem cells produce red blood cells, which carry oxygen; white blood cells, which protect the body from infections; and platelets, which are involved in blood clotting. As the abnormal hematopoietic stem cells multiply, populations of abnormal blood cells are formed, alongside normal blood cells produced by normal hematopoietic stem cells that do not have the genetic alteration. The proportion of abnormal blood cells in the body affects the severity of the signs and symptoms of PNH.

Some of the PIGA gene variants alter the numbers or types of protein building blocks (amino acids) in the PIG-A protein, impairing its function. Other variants result in the insertion of a premature stop signal in the genetic instructions for making PIG-A. As a result, an abnormally small protein, which is usually unstable and easily broken down, is produced.  A single variant in the PIGA gene can severely reduce or eliminate the function of PIG-A, because people have only one active copy of the PIGA gene in each cell. (The PIGA gene is located on the X-chromosome. Males have only one X chromosome. In females, who have two X chromosomes, a normal process called X-inactivation turns off one copy of the X chromosome, so that females also have only one active copy of the X chromosome in each body cell.) 

Cells with little or no functional PIG-A protein do not produce GPI anchors, and therefore are missing GPI-anchored proteins at the surface. Two important GPI-anchored proteins normally found on the surface of red blood cells protect them from being broken down during immune reactions. Without these proteins, the abnormal red blood cells are prematurely destroyed, leading to hemoglobinuria and other features of PNH. It is unclear how changes in the PIGA gene affect other types of blood cells.

Other disorders

Inherited (germline) variants in the PIGA gene can cause a disorder called PIGA deficiency, which refers to a spectrum of conditions with varied features and severity. Severely affected individuals typically have profound intellectual disability, seizures known as infantile spasms, weak muscle tone (hypotonia), distinctive facial features, and abnormalities of the brain and spinal cord (central nervous system) and other body systems. Less severely affected individuals have mild to moderate intellectual disability, infantile spasms, and other seizures that can typically be treated.

Germline variants are present in every cell of the body (in contrast to somatic variants that cause PNH [described above], which are only found in certain cells). Variants in the PIGA gene that cause PIGA deficiency reduce the function of the PIG-A protein in cells. Studies suggest that the amount of remaining PIG-A function determines the severity of the condition: very little PIG-A function causes more severe signs and symptoms. The changes reduce the number of GPI-anchored proteins, possibly on some cells but not others. Researchers suspect that a shortage (deficiency) of PIG-A function impairs the activity of cell structures called mitochondria, which are the energy-producing centers of cells, although the mechanism is not clear. Researchers are still determining how PIGA gene variants lead to the features of PIGA deficiency.

Simpson-Golabi-Behmel syndrome

MedlinePlus Genetics provides information about Simpson-Golabi-Behmel syndrome