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. 2000 Nov;67(5):1333-9.
doi: 10.1016/S0002-9297(07)62964-4. Epub 2000 Oct 2.

High frequency of alkaptonuria in Slovakia: evidence for the appearance of multiple mutations in HGO involving different mutational hot spots

A Zatková  1 , D B de Bernabé, H Poláková, M Zvarík, E Feráková, V Bosák, V Ferák, L Kádasi, S R de Córdoba
Affiliations

High frequency of alkaptonuria in Slovakia: evidence for the appearance of multiple mutations in HGO involving different mutational hot spots

A Zatková et al. Am J Hum Genet. 2000 Nov.

Erratum in

  • Am J Hum Genet 2001 May;68(5):1313

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.

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Figures

Figure 1
Figure 1
HGO haplotypes associated with the AKU mutations. The figure shows the allelic associations of 11 HGO intragenic polymorphisms for each of the 44 AKU Slovak chromosomes included in this study. The HGO polymorphic loci, ordered from 5′ to 3′, are IVS2+35, IVS2-218, IVS3-112, Ex4 (c407), IVS4+31, HGO-3, HGO-1, IVS5+25, IVS6+46, IVS11+18, and HGO-2. HGO-1, HGO-2, and HGO-3 are (CA)n or (CT)n dinucleotide repeats (Granadino et al. ; Beltran Valero de Bernabe et al. 1998). All other polymorphisms are diallelic SNPs (Beltran Valero de Bernabe et al. 1998; 1999a). AKU chromosomes are grouped by mutations. Each mutation group also includes the chromosomes described thus far outside Slovakia that carry the same AKU mutation. The chromosomes are identified by the pedigree code number, followed by a, b, c, or d (a and b indicates that the patient is an HGO homozygote). A thick vertical bar indicates the position, in the HGO haplotype, of each AKU mutation. A grey color code is used to identify the different HGO haplotypes. In very few instances, there was no information for the segregation of the alleles and both alleles were included in the haplotype. PR = present report.
Figure 2
Figure 2
Geographical distribution of the Slovak AKU mutations The figure shows the geographical locations for 37 of the 44 Slovak AKU chromosomes included in this report. No family data relative to geographical origins were available for the remaining 7 AKU chromosomes. The code used for the mutations is depicted in the right inset.
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References

Electronic-Database Information

    1. AKU database, http://www.cib.csic.es/~akudb/index.htm (for published and unpublished data of mutations and polymorphisms in the HGO gene)
    1. Entrez, http://www.ncbi.nlm.nih.gov/Entrez (for genomic sequences of HGO and its transcript; accession numbers AF000573 and AF045167, respectively)
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim (for AKU [MIM 203500]) - PubMed

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