Molecular Genetics of Alkaptonuria


Alkaptonuria (AKU), the first defined human genetic disease with a recessive trait, is caused by mutations within the homogentisate 1,2‐dioxygenase (HGD) gene (3q13.33). This prototypic inborn error of metabolism is characterised by typical bluish‐black pigmentation in connective tissue ochronosis and severe form of osteoarthritis caused by the deposition of ochronotic pigment in the joints. AKU belongs to a group of rare diseases (1:250 000–1:1 000 000), however, several ethnities were reported, where an increased incidence of AKU was observed (Slovakia, Dominican Republic, Jordan and India). Mutation analysis was so far performed in approximately 350 out of more than 650 worldwide reported AKU patients. Rather high heterogeneity was observed with 122 AKU‐causing mutations that are listed together with HGD polymorphisms in the global HGD mutation database ( Because HGD enzyme functions as hexamer, dimer of trimers, genotype/phenotype correlations are difficult to perform in this rare disease.

Key Concepts:

  • Alkaptonuria (AKU) is a prototypic inborn error in the metabolism of phenylalanine and tyrosine, characterised by the inability to metabolise homogentisic acid (HGA).

  • The raised HGA levels in plasma and extracellular fluid lead to ochronosis, the deposition of polymers of HGA as pigment (ochronotic pigment) in connective tissues including cartilage, heart valves and sclera.

  • Ochronosis leads to painful destruction of large weight‐bearing joints as well as fusion of the vertebrae, scoliosis and tendon and ligament ruptures.

  • AKU is caused by homozygous or compound heterozygous mutations in the homogentisate‐1,2‐dioxygenase gene (HGD) mapping to the chromosome 3q13.33.

  • AKU belongs to a group of rare diseases (1:250 000–1:1 000 000), however, several ethnities were reported, where an increased incidence of AKU was observed (Slovakia, Dominican Republic, Jordan and India).

  • In approximately 350 patients reported worldwide so far 122 different HGD mutations have been reported.

  • It was also shown that AKU is caused also by the apparently partial loss‐of‐function mutations, however, the heterozygous carriers of AKU are healthy.

  • HGD haplotype analysis helps to identify the origin of individual AKU‐causing mutations in different countries.

  • The triketone herbicide nitisinone or Orfadin inhibits the 4‐hydroxyphenylpyruvate dioxygenase enzyme, which produces HGA, thus, it can decrease HGA and should therefore potentially be able to modify AKU.

  • It has been shown that AKU is a novel type II AA amyloidosis, which opens new important perspectives for its therapy, since the control of the underlying inflammatory disorder can result in regression of the disease.

  • Research on ochronosis in this monogenic disease can help to elucidate the molecular pathogenesis of the more common varieties of osteoarthritis, particularly the biochemical and structural changes at its initial stages.

Keywords: AKU; alkaptonuria; HGD mutations; HGD mutation database; homogentisate 1,2‐dioxygenase

Figure 1.

Distribution within the HGD gene of 122 AKU mutations reported so far in about 350 families, 30 single nucleotide polymorphisms (SNPs) and 3 simple sequence repeats (SSRs). Variants IVS9‐56G>A** and IVS9‐17G>A** were published as mutations, but Vilboux et al. reported that they are most likely benign variants. Indeed, in the sample of patients variant IVS9‐17G>A has been found in homozygous state in the patient who also carried homozygous mutation P230S in exon 10. Mutations G115fs* (c.413_434+35del57) and V157fs* (c.470‐1_494del25) are caused by genomic deletions that are predicted to cause exon 6 and 8 skipping, respectively, thus leading to frameshift.

Figure 2.

Comparison of the proportions of HGD mutation types as identified worldwide and in Slovakia. Last column indicates the involvement of mutation hot spots.

Figure 3.

Haplotype analysis in family AKU_DB_61 where the segregation of 3 different AKU‐causing mutations can be followed.

Figure 4.

Map showing geographical distribution of the Slovak HGD mutations from 66 Slovak AKU chromosomes. The code used for the mutations is depicted in the right inset. Geographic origin was reconstructed based on the oldest family data available for the AKU patients. The chart in the right lower corner indicates the percentual proportion of individual mutation identified in Slovakia (out of 112 Slovak AKU chromosomes). In grey are indicated mutations that most likely originated in this country.



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Further Reading

Linder J, Miteva M and Romanelli P (2010) Pigmentary deposition disorders. In: Smoller BR and Rongioletti F (eds) Clinical and Pathological Aspects of Skin Diseases in Endocrine, Metabolic, Nutritional and Deposition Disease, pp. 171–180. New York: Springer New York.

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Zatkova, Andrea(Jan 2013) Molecular Genetics of Alkaptonuria. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024298]