Hartnup disorder is an autosomal recessive abnormality of renal and gastrointestinal neutral amino acid transport. A corresponding transport activity has been characterized in kidney and intestinal cells and named system B0. The failure to resorb amino acids in this disorder is thought to be compensated by a protein-rich diet. However, in combination with a poor diet and other factors, more severe symptoms can develop in Hartnup patients, including a photosensitive pellagra-like skin rash, cerebellar ataxia and other neurological symptoms. Homozygosity mapping in a Japanese family and linkage analysis on six Australian pedigrees placed the Hartnup disorder gene at a locus on chromosome 5p15. This fine mapping facilitated a candidate gene approach within the interval, which resulted in the cloning and characterization of a novel member of the sodium-dependent neurotransmitter transporter family (B0AT1, SLC6A19) from mouse and human kidney, which shows all properties of system B0. Flux experiments and electrophysiological recording showed that the transporter is Na+ dependent and Cl− independent, electrogenic and actively transports most neutral amino acids. In situ hybridization showed strong expression in intestinal villi and in the proximal tubule of the kidney. Expression of B0AT1 was restricted to kidney, intestine and skin. A total of ten mutations have been identified in SLC6A19 that co-segregate with disease in the predicted recessive manner, with the majority of affected individuals being compound heterozygotes. These mutations lead to altered neutral amino acid transport function compared to the wild-type allele in vitro. One of the mutations occurs in members of the original Hartnup family described in 1956, thereby defining SLC6A19 as the ‘Hartnup’-gene.
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Conference Article|
February 01 2005
Neutral amino acid transport in epithelial cells and its malfunction in Hartnup disorder
S. Bröer;
S. Bröer
1
*School of Biochemistry & Molecular Biology, Australian National University, Canberra, ACT 0200, Australia
1To whom correspondence should be addressed (email stefan.broeer@anu.edu.au).
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J.A. Cavanaugh;
J.A. Cavanaugh
†Medical Genetics Research Unit, ANU Medical School, The Canberra Hospital, Woden, ACT 2607, Australia
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J.E.J. Rasko
J.E.J. Rasko
‡Gene Therapy, Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney and Sydney Cancer Centre, Royal Prince Alfred Hospital, Locked Bag 6, Newtown, NSW 2042, Australia
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Publisher: Portland Press Ltd
Received:
October 22 2004
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2005 The Biochemical Society
2005
Biochem Soc Trans (2005) 33 (1): 233–236.
Article history
Received:
October 22 2004
Citation
S. Bröer, J.A. Cavanaugh, J.E.J. Rasko; Neutral amino acid transport in epithelial cells and its malfunction in Hartnup disorder. Biochem Soc Trans 1 February 2005; 33 (1): 233–236. doi: https://doi.org/10.1042/BST0330233
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