HPD

The HPD gene provides instructions for making an enzyme called 4-hydroxyphenylpyruvate dioxygenase. This enzyme is abundant in the liver, and smaller amounts are found in the kidneys. It is one of a series of enzymes needed to break down the amino acid tyrosine, a protein building block found in many foods. Specifically, 4-hydroxyphenylpyruvate dioxygenase converts a tyrosine byproduct called 4-hydroxyphenylpyruvate to homogentisic acid. In reactions with other enzymes in the series, homogentisic acid is broken down to smaller molecules that are either excreted by the kidneys or used to produce energy.

tyrosinemia - caused by mutations in the HPD gene

Researchers have identified several HPD mutations that cause type III tyrosinemia. Some of these mutations change one of the building blocks (amino acids) used to make the 4-hydroxyphenylpyruvate dioxygenase enzyme. Other mutations lead to an unusually small enzyme that is missing many amino acids. As a result of these mutations, the activity of the 4-hydroxyphenylpyruvate dioxygenase enzyme is unusually low or absent. With inadequate enzyme activity, researchers believe that 4-hydroxyphenylpyruvate is converted to a toxic compound instead of homogentisic acid. As this toxic compound builds up, it can impair cell functions, particularly in the nervous system. Impaired nerve cells could lead to the characteristic features of type III tyrosinemia, which include intellectual disability, seizures, and problems with balance and coordination.

other disorders - caused by mutations in the HPD gene

One particular HPD mutation can cause a rare condition called hawkinsinuria. In infants, this condition is characterized by a failure to gain weight and grow at the expected rate (failure to thrive) and abnormally high acid levels in the blood (acidosis). The HPD mutation replaces the amino acid alanine with the amino acid threonine at position 33 in the 4-hydroxyphenylpyruvate dioxygenase enzyme. This mutation (written as Ala33Thr or A33T) reduces the activity of the 4-hydroxyphenylpyruvate dioxygenase enzyme. As a result, 4-hydroxyphenylpyruvate is not efficiently converted to homogentisic acid. Instead, some 4-hydroxyphenylpyruvate forms an unusual sulfur-containing amino acid called hawkinsin. It remains unclear how the HPD mutation leads to the features of hawkinsinuria.