Further evidence for allelic heterogeneity in hartnup disorder

Dimitar N. Azmanov, Sonja Kowalczuk, Helen Rodgers, Christiane Auray-Blais, Robert Giguère, John E.J. Rasko, Stefan Bröer, Juleen A. Cavanaugh

    Research output: Contribution to journalArticlepeer-review

    23 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1217-1221
    Number of pages5
    JournalHuman Mutation
    Volume29
    Issue number10
    DOIs
    Publication statusPublished - Oct 2008

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