title: Further evidence for allelic heterogeneity in Hartnup disorder.
abstract: Hartnup disorder is an autosomal recessive impairment of amino acid transport in kidney and intestine. Mutations in SLC6A19 have been shown to cosegregate with the disease in the predicted recessive manner; however, in two previous studies (Seow et al., Nat Genet 2004;36:1003-1007; Kleta et al., Nat Genet 2004;36:999-1002), not all causative alleles were identified in all affected individuals, raising the possibility that other genes may contribute to Hartnup disorder. We have now investigated six newly acquired families of Australian and Canadian (Province of Quebec) origin and resequenced the entire coding region of SLC6A19 in families with only a single disease allele identified. We also studied one American family in whom no mutations had been identified in a previous study (Kleta et al., Nat Genet 2004;36:999-1002). We have identified seven novel mutations in SLC6A19 that show functional obliteration of the protein in vitro, explaining Hartnup disorder in all reported families so far. We demonstrate that Hartnup disorder is allelically heterogeneous with two mutated SLC6A19 alleles, whether identical or not, necessary for manifestation of the characteristic aminoaciduria in affected individuals. This study resolves the previous hypothesis that other genes contribute to the Hartnup phenotype.
authors.affiliation: Medical Genetics Research Unit, Australian National University (ANU) Medical School, Canberra, Australian Capital Territory (ACT), Australia. Dimitar.Azmanov@anu.edu.au
authors.forename: Dimitar N
authors.initials: DN
authors.lastname: Azmanov
authors.forename: Sonja
authors.initials: S
authors.lastname: Kowalczuk
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: John E J
authors.initials: JE
authors.lastname: Rasko
authors.forename: Stefan
authors.initials: S
authors.lastname: Bröer
authors.forename: Juleen A
authors.initials: JA
authors.lastname: Cavanaugh
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics*; D001315:Australia; D001483:Base Sequence; D005190:Family; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D006239:Haplotypes; D006250:Hartnup Disease / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C491436:SLC6A19 protein, human