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Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19

Nature Genetics volume 36, pages 1003–1007 (2004)Cite this article

Abstract

Hartnup disorder (OMIM 234500) is an autosomal recessive abnormality of renal and gastrointestinal neutral amino acid transport noted for its clinical variability. We localized a gene causing Hartnup disorder to chromosome 5p15.33 and cloned a new gene, SLC6A19, in this region. SLC6A19 is a sodium-dependent and chloride-independent neutral amino acid transporter, expressed predominately in kidney and intestine, with properties of system B0. We identified six mutations in SLC6A19 that cosegregated with disease in the predicted recessive manner, with most affected individuals being compound heterozygotes. The disease-causing mutations that we tested reduced neutral amino acid transport function in vitro. Population frequencies for the most common mutated SLC6A19 alleles are 0.007 for 517G → A and 0.001 for 718C → T. Our findings indicate that SLC6A19 is the long-sought gene that is mutated in Hartnup disorder; its identification provides the opportunity to examine the inconsistent multisystemic features of this disorder.

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Figure 1: Ion and voltage dependence and substrate specificity of SLC6A19 confirm that it has the predicted profile for system B0.
Figure 2: Inheritance of two different mutations of SLC6A19 in a single pedigree (pedigree 2) in which the son (2.3) and first daughter (2.4) have the Hartnup disorder hyperaminoaciduria phenotype.
Figure 3: Leucine transport activities in mutant SLC6A19 proteins.
Figure 4: Schematic representation of mutations in the system B0 transporter SLC6A19.

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Acknowledgements

The Australian Hartnup Consortium represented in this publication thanks B. Wilcken for undertaking the original neonatal screening program in NSW that facilitated this study. We thank D.I.K. Martin and A. Basten for critical reading of the manuscript; the participating families for their generous consent; and C. Ng, J. Lai, O.T. Ooi and S. Kowalzcuk for technical assistance.

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Author notes

  1. Heng F Seow and Stefan Bröer: These authors contributed equally to this work.

Authors and Affiliations

  1. Gene Therapy, Centenary Institute of Cancer Medicine & Cell Biology, University of Sydney, NSW 2042, Australia

    Heng F Seow, Charles G Bailey, Simon J Potter & John E J Rasko

  2. School of Biochemistry & Molecular Biology, Faculty of Science, Australian National University, Canberra, ACT 0200, Australia

    Stefan Bröer & Angelika Bröer

  3. Medical Genetics Research Unit, Australian National University Medical School, The Canberra Hospital, Canberra, ACT 2606, Australia

    Juleen A Cavanaugh

  4. Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia

    John E J Rasko

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  1. Heng F Seow
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Correspondence to John E J Rasko.

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Supplementary information

Supplementary Fig. 1

Hartnup disorder pedigrees. (PDF 46 kb)

Supplementary Table 1

Regions containing candidates studied by linkage analysis. (PDF 5 kb)

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Seow, H., Bröer, S., Bröer, A. et al. Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nat Genet 36, 1003–1007 (2004). https://doi.org/10.1038/ng1406

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