Molecular Genetics of Alkaptonuria (original) (raw)

eLS, 2013

Abstract

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 (http://hgddatabase.cvtisr.sk/). 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

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