Further evidence for allelic heterogeneity in Hartnup disorder

Dimitar Azmanov, S. Kowalczuk, H.J. Rodgers, C. Auray-Blais, R Giguère, J.E.J. Rasko, S Broër, J.A. Cavanaugh

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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. Hum Mutat 0,1–5, 2008. © 2008 Wiley-Liss, Inc.
Original languageEnglish
Pages (from-to)1217-21
JournalHuman Mutation
Volume29
Issue number10
DOIs
Publication statusPublished - 2008

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Hartnup Disease
Viverridae
Alleles
Mutation
Quebec
Genes
Intestines
Phenotype
Kidney
Amino Acids
Proteins

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Azmanov, D., Kowalczuk, S., Rodgers, H. J., Auray-Blais, C., Giguère, R., Rasko, J. E. J., ... Cavanaugh, J. A. (2008). Further evidence for allelic heterogeneity in Hartnup disorder. Human Mutation, 29(10), 1217-21. https://doi.org/10.1002/humu.20777
Azmanov, Dimitar ; Kowalczuk, S. ; Rodgers, H.J. ; Auray-Blais, C. ; Giguère, R ; Rasko, J.E.J. ; Broër, S ; Cavanaugh, J.A. / Further evidence for allelic heterogeneity in Hartnup disorder. In: Human Mutation. 2008 ; Vol. 29, No. 10. pp. 1217-21.
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Azmanov, D, Kowalczuk, S, Rodgers, HJ, Auray-Blais, C, Giguère, R, Rasko, JEJ, Broër, S & Cavanaugh, JA 2008, 'Further evidence for allelic heterogeneity in Hartnup disorder' Human Mutation, vol. 29, no. 10, pp. 1217-21. https://doi.org/10.1002/humu.20777

Further evidence for allelic heterogeneity in Hartnup disorder. / Azmanov, Dimitar; Kowalczuk, S.; Rodgers, H.J.; Auray-Blais, C.; Giguère, R; Rasko, J.E.J.; Broër, S; Cavanaugh, J.A.

In: Human Mutation, Vol. 29, No. 10, 2008, p. 1217-21.

Research output: Contribution to journalArticle

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T1 - Further evidence for allelic heterogeneity in Hartnup disorder

AU - Azmanov, Dimitar

AU - Kowalczuk, S.

AU - Rodgers, H.J.

AU - Auray-Blais, C.

AU - Giguère, R

AU - Rasko, J.E.J.

AU - Broër, S

AU - Cavanaugh, J.A.

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AB - 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. Hum Mutat 0,1–5, 2008. © 2008 Wiley-Liss, Inc.

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JO - Human Mutation

JF - Human Mutation

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Azmanov D, Kowalczuk S, Rodgers HJ, Auray-Blais C, Giguère R, Rasko JEJ et al. Further evidence for allelic heterogeneity in Hartnup disorder. Human Mutation. 2008;29(10):1217-21. https://doi.org/10.1002/humu.20777