title: Persistence of the common Hartnup disease D173N allele in populations of European origin.
abstract: Hartnup disorder is an aminoaciduria that results from mutations in the recently described gene SLC6A19 on chromosome 5p15.33. The disease is inherited in a simple recessive manner and ten different mutations have been described to date. One mutation, the D173N allele, is present in 42% of Hartnup chromosomes from apparently unrelated families from both Australia and North America. We report an investigation of the origins of the D173N allele using a unique combination of variants including SNPs, microsatellites, and a VNTR across 211 Kb spanning the SLC6A19 locus. All individuals who carry the mutant allele share an identical core haplotype suggesting a single common ancestor, indicating that the elevated frequency of the D173N allele is not a result of recurrent mutation. Analyses of these data indicate that the allele is more than 1000 years old. We compare the reasons for survival of this allele with other major alleles in some other common autosomal recessive diseases occurring in European Caucasians. We postulate that survival of this allele may be a consequence of failure of the allele to completely inactivate the transport of neutral amino acids.
authors.affiliation: Medical Genetics Research Unit, ANU Medical School, Canberra, Australia.
authors.forename: Dimitar N
authors.initials: DN
authors.lastname: Azmanov
authors.forename: Helen
authors.initials: H
authors.lastname: Rodgers
authors.forename: Christiane
authors.initials: C
authors.lastname: Auray-Blais
authors.forename: Robert
authors.initials: R
authors.lastname: Giguère
authors.forename: Charles
authors.initials: C
authors.lastname: Bailey
authors.forename: Stefan
authors.initials: S
authors.lastname: Bröer
authors.forename: John E J
authors.initials: JE
authors.lastname: Rasko
authors.forename: Juleen A
authors.initials: JA
authors.lastname: Cavanaugh
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics*; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D018703:Founder Effect; D005808:Genes, Recessive; D006239:Haplotypes; D006250:Hartnup Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D018598:Minisatellite Repeats; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D013997:Time Factors; D044465:White People / Q000235:genetics
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C491436:SLC6A19 protein, human