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Multiple origins for phenylketonuria in Europe
R C Eisensmith1, Y Okano, M Dasovich
1Howard Hughes Medical Institute, Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030.
American Journal of Human Genetics
|December 1, 1992
Summary
Phenylketonuria (PKU) arises from phenylalanine hydroxylase (PAH) deficiency. Multiple distinct origins of common PKU mutations across European ethnic groups suggest varied historical genetic events.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Phenylketonuria (PKU) is an amino acid metabolism disorder caused by phenylalanine hydroxylase (PAH) deficiency.
- PKU exhibits high genetic heterogeneity with over 60 identified mutations in the PAH gene.
Purpose of the Study:
- To investigate the haplotype associations, frequencies, and distributions of five prevalent PAH mutations in European populations.
- To explore the role of genetic mechanisms in the geographical distribution of major PKU alleles.
Main Methods:
- Analysis of haplotype associations for five common PAH mutations (R158Q, R261Q, IVS10nt546, R408W, IVS12n1).
- Examination of mutation distributions and relative frequencies across a comprehensive European sample.
- Utilized Restriction Fragment Length Polymorphisms (RFLPs) to define chromosomal haplotypes.
Main Results:
- Each of the five studied PAH mutations showed strong association with a single chromosomal haplotype.
- Evidence suggests each mutation originated from a distinct founding event between several hundred to thousands of years ago.
- Significant variations in allele frequencies and distributions across Europe allowed localization of four founding events to specific ethnic subgroups.
Conclusions:
- The findings support the hypothesis of multiple, geographically and ethnically distinct origins for PKU within the European population.
- Specific PAH mutations likely arose independently in different ancestral European groups.