High Frequency of Alkaptonuria in Slovakia: Evidence for the Appearance of Multiple Mutations in HGO Involving Different Mutational Hot Spots

Abstract

Alkaptonuria (AKU) is an autosomal recessive disorder caused by the deficiency of homogentisate 1,2 dioxygenase (HGO) activity. AKU shows a very low prevalence (1:100,000-250,000) in most ethnic groups. One notable exception is in Slovakia, where the incidence of AKU rises to 1:19,000. This high incidence is difficult to explain by a classical founder effect, because as many as 10 different AKU mutations have been identified in this relatively small country. We have determined the allelic associations of 11 HGO intragenic polymorphisms for 44 AKU chromosomes from 20 Slovak pedigrees. These data were compared to the HGO haplotype data available in our laboratory for >80 AKU chromosomes from different European and non-European countries. The results show that common European AKU chromosomes have had only a marginal contribution to the Slovak AKU gene pool. Six of the ten Slovak AKU mutations, including the prevalent G152fs, G161R, G270R, and P370fs mutations, most likely originated in Slovakia. Data available for 17 Slovak AKU pedigrees indicate that most of the AKU chromosomes have their origins in a single very small region in the Carpathian mountains, in the northwestern part of the country. Since all six Slovak AKU mutations are associated with HGO mutational hot spots, we suggest that an increased mutation rate at the HGO gene is responsible for the clustering of AKU mutations in such a small geographical region.

Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on ‘black bone disease’ in Italy

“…13 Although a clear founder effect was observed in the Dominican republic, 11 in Slovakia, already 13 different HGD variants affecting function are reported in 121 AKU chromosomes, though most of the patients in this country come from a previously genetically isolated region. [7][8][9][32][33][34][35] The most frequent variant found in Slovakia is p.Gly161Arg, present in 45% of all AKU alleles (HGD mutation database).…”

“…[6][7][8] Some of the reported HGD variants are spread throughout the world, such as c.175delA (p.(Ser59Alafs*52)), one of the first identified AKU mutations, c.899T4G (p.(Val300Gly)). 7 On the other hand, there are variants rather specific for some countries or regions; for example, c.342+1G4A (ivs5+1G4A) for Slovakia and the Czech Republic, 9 c.87+1G4A (ivs2+1G4A) for the gypsy community Narikuravar in India 10 or c.360T4G (p.(Cys120Trp)) for the Dominican Republic. 11 So far, about 950 AKU patients have been reported in 61 countries worldwide (AKU Society, www.akusociety.org).…”

Properties and Function of Pyomelanin

“…Since bacteria need only small quantities of this polymer to enhance their electron shuttling capacity, the low detection limit required to identify environmentally relevant quantities marginalizes a direct analytical chemical approach. However, given that numerous strains of soil bacteria are known to produce pyomelanin and if the rate of mutation of the HGA-oxidase gene is similar in bacteria to that in humans (1:100,000 -250,000) (Zatkova, et al 2000), pyomelaninproducing bacteria may be ubiquitous in the environment. If present in a particular environment, pyomelanin producers may be too low in number to contribute to significant electron transfer and hence metal transformation.…”

Urinary Homogentisic Acid in Alkaptonuric and Healthy Children

“…It was interpreted as a Mendelian trait by Garrod and Bateson. Prevalence of AKU is relatively low in Europe (1:100 000 -250 000) but increased AKU prevalence (1:19 000) has been described recently in a geographical region of Slovakia (3).…”