Heme is a red pigment composed of iron linked to a chemical called protoporphyrin. Heme has important functions in the body. The largest amounts of heme are in the form of hemoglobin, found in red blood cells and bone marrow. Hemoglobin carries oxygen from the lungs to all parts of the body. In the liver, heme is a component of proteins that break down hormones, medications, and other chemicals and keep liver cells functioning normally. Heme is an important part of nearly every cell in the body.

• Blisters and sores on sun exposed skin
• Darkened or lightened skin patches
• Stomach pain
• Nausea and vomiting
• Constipation
• Muscle weakness
• Seizures
• Mental changes

Variegate porphyria occurs when the PPOX gene is not working correctly. DNA changes known as pathogenic variants are responsible for making genes work incorrectly or sometimes, not at all. Not everyone who has a PPOX variant will have symptoms of variegate porphyria.

Normal Function

The PPOX gene provides instructions for making an enzyme known as protoporphyrinogen oxidase. This enzyme is involved in the production of a molecule called heme. Heme is vital for all of the body's organs, although it is most abundant in the blood, bone marrow, and liver. Heme is an essential component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood).

The production of heme is a multi-step process that requires eight different enzymes. Protoporphyrinogen oxidase is responsible for the seventh step in this process, in which two hydrogen atoms are removed from protoporphyrinogen IX (the product of the sixth step) to form protoporphyrin IX. In the final step, another enzyme modifies protoporphyrin IX by inserting an iron atom to produce heme.

Health Conditions Related to Genetic Changes

Porphyria

More than 130 mutations in the PPOX gene have been identified in people with a form of porphyria called variegate porphyria. A particular PPOX gene mutation is found in about 95 percent of South African families with this form of the disorder. The mutation changes a single protein building block (amino acid) in protoporphyrinogen oxidase, replacing the amino acid arginine with the amino acid tryptophan at position 59 (written as Arg59Trp or R59W).

Mutations in the PPOX gene reduce the activity of protoporphyrinogen oxidase, allowing compounds called porphyrin precursors to build up in the body. These compounds are formed during the normal process of heme production, but reduced activity of protoporphyrinogen oxidase allows them to accumulate to toxic levels. Nongenetic factors such as certain drugs, alcohol, dieting, as well as other genetic factors that have not been identified, also contribute to the characteristic features of variegate porphyria.

Other Names for This Gene

• PPO
• PPOX_HUMAN
• protoporphyrinogen dehydrogenase
• protoporphyrinogen IX oxidase
• protoporphyrinogenase
• protox

Genomic Location

Variegate porphyria is inherited in an autosomal dominant pattern. All individuals inherit two copies of each gene. Autosomal means the gene is found on one of the numbered chromosomes found in both sexes. Dominant means that only one pathogenic variant on one copy of a gene is necessary to have the condition. The variant can be inherited from either parent. Sometimes an autosomal dominant condition occurs because of a new genetic variant (de novo) and there is no history of this condition in the family.

Each child of an individual with an autosomal dominant condition has a 50% or 1 in 2 chance of inheriting the variant and the condition. Typically, children who inherit a dominant variant will have the condition, but they may be more or less severely affected than their parent. Sometimes a person may have a gene variant for an autosomal dominant condition and show no signs or symptoms of the condition.