Paroxysmal nocturnal hemoglobinuria

Variants (also known as mutations) in the PIGT gene cause a rare form of paroxysmal nocturnal hemoglobinuria (PNH), which is a condition that affects blood cells. People with PNH have episodes of blood in the urine (hemoglobinuria) that results from the breakdown of red blood cells. Other blood cell abnormalities also occur. In addition, individuals with PIGT-related PNH have abnormal inflammation, which can cause recurrent aseptic meningitis (which is inflammation of the membranes surrounding the brain and spinal cord  not caused by infections); a red, itchy rash (known as hives or urticaria); joint pain (arthralgia); or inflammatory bowel disease.

Affected individuals are born with a variant in one copy of the PIGT gene. This inherited variant is known as a germline variant and is present in every cell of the body. A second alteration that deletes the other (normal) copy of the PIGT gene is acquired during the person’s lifetime. This second variant, known as a somatic variant, occurs in a blood-forming cell called a hematopoietic stem cell. This variant is found only in the hematopoietic stem cell and blood cells produced from that cell. Together, these PIGT gene variants severely reduce or eliminate the function of the PIG-T protein. As a result, GPI anchors are not attached to proteins inside cells. The GPI anchors without proteins are present at the surface of the cell. The shortage of certain proteins at the cell surface alters cell functions. Specifically, proteins that normally protect red blood cells from being broken down are missing. The red blood cells are prematurely destroyed, leading to a shortage of red blood cells (hemolytic anemia) and blood in the urine.

Studies show that GPI anchors with no attached proteins trigger inflammation in the body, leading to the inflammatory features in individuals with PIGT-related PNH.

Other disorders

Variants in the PIGT gene also cause a rare condition called multiple congenital anomalies-hypotonia-seizures syndrome 3. Affected individuals have delayed development; seizures; low muscle tone (hypotonia); distinct facial features; and abnormalities that are present from birth (congenital), typically involving the heart, bones, urinary system, or digestive system.

Individuals with this condition inherit two altered copies of the PIGT gene, one from each parent. The variants impair the function of the PIG-T protein, reducing the levels of proteins attached to the cell surface by GPI anchors. Researchers suspect that a shortage of proteins important for development on the surface of cells impairs the normal development of many body systems, leading to the varied signs and symptoms of multiple congenital anomalies-hypotonia-seizures syndrome 3.