Mutations in the HGD gene cause alkaptonuria. The HGD gene provides instructions for making an enzyme called homogentisate oxidase. This enzyme helps break down the amino acids phenylalanine and tyrosine, which are important building blocks of proteins. Mutations in the HGD gene impair the enzyme's role in this process. As a result, a substance called homogentisic acid, which is produced as phenylalanine and tyrosine are broken down, accumulates in the body. Excess homogentisic acid and related compounds are deposited in connective tissues, which causes cartilage and skin to darken. Over time, a buildup of this substance in the joints leads to arthritis. Homogentisic acid is also excreted in urine, making the urine turn dark when exposed to air.

Normal Function

The HGD gene provides instructions for making an enzyme called homogentisate oxidase, which is active chiefly in the liver and kidneys. This enzyme participates in a step-wise process that breaks down two protein building blocks (amino acids), phenylalanine and tyrosine, when they are no longer needed or are present in excess. These two amino acids also play a role in making certain hormones, pigments, and brain chemicals called neurotransmitters.

Homogentisate oxidase is responsible for a specific step in the breakdown of phenylalanine and tyrosine. Previous steps convert the two amino acids into a molecule called homogentisic acid. Homogentisate oxidase adds two oxygen atoms to homogentisic acid, converting it to another molecule called maleylacetoacetate. Other enzymes break down maleylacetoacetate into smaller molecules that are later used for energy or to make other products that can be used by the body.

Health Conditions Related to Genetic Changes

Alkaptonuria

More than 65 mutations in the HGD gene have been identified in people with alkaptonuria. Most of these mutations change single amino acids used to build the homogentisate oxidase enzyme. For example, a substitution of the amino acid valine for the amino acid methionine at protein position 368 (also written as Met368Val) is the most common HGD mutation in European populations.

Mutations in the HGD gene inactivate homogentisate oxidase by changing its structure. Without a functional version of this enzyme, phenylalanine and tyrosine are not broken down properly and homogentisic acid builds up in the body. Excess homogentisic acid and related compounds are deposited in connective tissues such as cartilage and skin, which causes them to darken. Over time, a buildup of this substance in the joints leads to arthritis. Homogentisic acid is also excreted in urine, making the urine turn dark when exposed to air.

Other Names for This Gene

• AKU
• HGD_HUMAN
• HGO
• homogentisate 1,2-dioxygenase (homogentisate oxidase)
• Homogentisic acid oxidase
• homogentisicase

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

This condition is rare, affecting 1 in 250,000 to 1 million people worldwide. Alkaptonuria is more common in certain areas of Slovakia (where it has an incidence of about 1 in 19,000 people) and in the Dominican Republic.