title: Allelic heterogeneity of alkaptonuria in Central Europe.
abstract: Defects of the homogentisate 1,2 dioxygenase (HGO; E.C. No. 1.13.11.5) have been identified as the molecular cause of alkaptonuria in humans (AKU) and the aku mouse. Here, we report on the genetic basis of 30 AKU patients from Central Europe. In addition to five mutations described previously, we have detected five novel HGO mutations. Recombinant expression of mutated HGO enzymes in E. coli demonstrates the inactivating effect of three of these mutations. A genetic epidemiologic study in Slovakia, the country with the highest incidence of alkaptonuria, demonstrates that two recurrent mutations (c.183-1G > A and Glyl61Arg) are found on more than 50% of AKU chromosomes. An analysis of the allelic association with intragenic DNA markers and of the geographic origins of the AKU chromosomes suggests that several independent founders have contributed to the gene pool, and that subsequent genetic isolation is likely to be responsible for the high prevalence of alkaptonuria in Slovakia.
authors.affiliation: Department of Human Genetics, University of Würzburg, Biozentrum, Germany. crm@biozentrum.uni-wuerzburg.de
authors.forename: C R
authors.initials: CR
authors.lastname: Müller
authors.forename: A
authors.initials: A
authors.lastname: Fregin
authors.forename: S
authors.initials: S
authors.lastname: Srsen
authors.forename: K
authors.initials: K
authors.lastname: Srsnova
authors.forename: B
authors.initials: B
authors.lastname: Halliger-Keller
authors.forename: U
authors.initials: U
authors.lastname: Felbor
authors.forename: E
authors.initials: E
authors.lastname: Seemanova
authors.forename: W
authors.initials: W
authors.lastname: Kress
mesh_terms: D000474:Alkaptonuria / Q000208:ethnology / Q000235:genetics*; D000483:Alleles; D017398:Alternative Splicing; D018076:DNA, Complementary / Q000032:analysis; D005060:Europe / Q000453:epidemiology; D005091:Exons; D018703:Founder Effect; D018740:Genetic Heterogeneity; D005819:Genetic Markers; D005820:Genetic Testing; D006801:Humans; D007438:Introns; D009154:Mutation; D020125:Mutation, Missense; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors
chemical_list: D018076:DNA, Complementary; D005819:Genetic Markers; D011994:Recombinant Proteins