Genetics of alkaptonuria – rare disease caused by HGD gene

Everything from tuberculosis bacterium to wonderful butterfly digests proteins and protein building blocks – amino acids. The digestion process comprises many steps performed by numerous molecules. Disruption to any of those molecules leads to disorder affecting various cells and tissues. Alkaptonuria is one of those disorders, called metabolic disorders. The cause is a mutation to HGD gene that disrupts degradation process of two amino acids: tyrosine and phenylalanine.

HGD gene alteration in chromosome 3 – cause of alkaptonuria

Alkaptonuria is a rare disease, inborn in one person per every 20,000-1,000,000 – which equals to the risk of 0,005% – 0,0001%. Its cause are various mutations to HGD gene. Currently there are known 181 variants of mutations (available at Andrea Zatkova database).

HGD gene is located on chromosome 3 long arm, consists of 14 exons (distinct sections) and 54,363 base pairs (A, T, G or C). Mutations occur in any of exons and also between exons. The most common mutations are missense substitions in 8th exon – substition of one base pair where original information (sense) is lost and the product of the gene is therefore disrupted.

Inheritance pattern is consistent with Mendelian rules regarding recessive transfer:

  • Each parent has two copies of HGD gene (humans are diploid organisms which means that we have two copies of every chromosome and of genes on it),
  • At least one of the two copies is mutated (one copy if the disorder is not apparent in parent, two if parent already suffers from the disorder),
  • During conception, each parent gives only one copy of the two copies to offspring,
  • By chance, 1 in 4 children inherits two mutated copies and develops alkaptonuria.

Mechanism of alkaptonuria: homogentisic acid accumulation

In the physiological state, the HGD gene produces a molecule (enzyme homogentisate 1,2-dioxygenase) governing one step in the processing of phenylalanine and tyrosine (2 of 22 amino acids building all known proteins). At the biochemical level, the enzyme oxidises homogentisic acid to 4-maleylacetoacetate and allows two further steps to reach full breakdown of the amino acids. At the body level, these reactions are essential for food digestion, hormone decomposition, pigment turnover.

When HGD enzyme is malfunctioning, the degradation process stops at 4th step out of 6. Instead of accumulating products of complete amino acid degration (which then would be used), cells accumulate intermediate molecule: homogentisic acid (which is not used). Accumulation of homogentisic acid translates to symptoms of alkaptonuria.

Symptoms of alkaptonuria: black urine, ochronosis, arthritis

The disorder may manifest itself at any age by:

  • Dark urine or black urine
  • Black sklera
  • Blue-black pigment of the cartilaginous tissues
  • Skin pigmentation
  • Joint and spine arthritis
  • Heart valves damage
  • Coronary artery calcification
  • Formation of kidney and renal stones

In addition to visual symptoms, sequencing and analysis of HGD gene is crucial for proper diagnosis.

Genetic therapy of alkaptonuria: in the future

There are no known genetic therapies or trials trying to correct mutations in HGD gene. It is likely that in the future there will be developed procedures aiming to replace disfunctional gene with normal gene. Similar techniques curing other Mendelian disorders are currently being developed.

Brief history: the first of all

Shortly after the rediscovery of Mendel’s research, Archibald Garrod stated that alkaptonuria follows Mendelian inheritance. His motivation was his father who suffered from the disorder and might pass to Archibald gene copy with a mutation. Findings of the genetic basis of alkaptonuria were published in 1902. It was the first genetic disorder described.

However, specific mutations were detected over ninety years later. Because of the rarity of the disease, science showed the first two amino acid changes of HGD gene in 1996.

Since 1996, sequencing reached over 800 hundred people with alkaptonuria. Systematic clinical work revealed 181 various mutatons leading to the disease. Nowadays there are many societes and organizations supporting a process of diagnosis and people after diagnosis: US AKU Society, UK AKU Society, French ALCAP, Italian AIMAKU, German DSAKU, Slovak and Czech AKUSSaC.

Last revised & updated: 16th September 2020.


[1] “Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria”, T. Vilboux et al., 2009, doi:10.1002/humu.21120.
[2] “Mutation Screening of the HGD Gene Identifies a Novel Alkaptonuria Mutation with Significant Founder Effect and High Prevalence”, S. Sakthivel1 et al., 2014, doi:10.1111/ahg.12055.
[3] OMIM Entry #203500.
[4] “Alkaptonuria: an example of a “fundamental disease” – a rare disease with important lessons for more common disorders”, J. Gallagher et al., 2016, doi:10.1016/j.semcdb.2016.02.020.