Current view on genetics of alkaptonuria

Authors: V. Bošák
Authors‘ workplace: Národný ústav reumatických chorôb, Piešťany, Slovenská republika, Fakulta zdravotníctva a sociálnej práce, Trnavská univerzita, Trnava, Slovenská republika
Published in: Čes. Revmatol., 18, 2010, No. 2, p. 92-96.
Category: Overview Reports


Alkaptonuria (AKU) is a monogenic, autosomal recessive inherited disorder that is due to a defect of the enzyme homogentisate oxidase. As a result, homogentisic acid accumulates in the organism and is excreted in urine. Its polymer, a blue-white ochronotic pigment, is deposited in cartilage and connective tissues, and causes their pigmentation (ochronosis). From a clinical perspective, the spine and large joints are most severely involved. Absence of biological activity of the hepatic enzyme homogentisate 1,2-dioxygenase (HGD) represents the biochemical basis of AKU. HGD participates in catabolism of phenylalanine and tyrosine. The HGD coding gene consists of 14 exons, 13 introns, and is located on the long arm of chromosome 3 (3q21-23). The complete length of nucleotide sequence is 54 363 bp, whereas the coding portion of the gene is only 1 715 bp long. The HGD gene is tissue specifically expressed mainly in the liver and kidneys. The defect of HGD is not caused by one mutation only, as was originally assumed. Currently, there are at least 67 known mutations, most of which are rare and specific for certain localities or families. All of them lead to a complete loss of enzymatic activity of HGD. In the Slovak population, 10 different mutations of the HGD gene were found, six of which (G270R, G161R, G152fs, P370fs, S47L, IVS5+1G→A) probably originate from a Slovak region called Kysuce. These mutations were induced by some environmental or nutritional factors. Subsequent genetic drift and isolation caused an increase in frequency of these mutations, which leaded to higher occurrence of AKU. Slovakia is characterised by the highest occurrence of AKU worldwide (incidence rate in the Slovak new-born population is 1:19 000). Molecular genetic findings in AKU have been used in DNA diagnostics, in screening for healthy carriers (heterozygotes), and could be promising towards the development of gene therapy of AKU.

Key words:
Alkaptonuria (AKU), genetics of AKU, homogentisate 1,2-dioxygenase (HGD), HGD gene, mutations


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Dermatology & STDs Paediatric rheumatology Rheumatology
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