Hereditary Pellagra-Like Skin Rash With Temporary Cerebellar Ataxia, Constant Renal Amino-Aciduria, and Other Bizarre Biochemical Features

Baron, D N; Dent, C. E.; Harris, Heather A.; Hart, EC; Jepson, J.B.

doi:10.1016/s0140-6736(56)91914-6

Cited by 379 publications

(95 citation statements)

References 10 publications

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“…10, 36 Hartnup's disorder is a hereditary familial disease characterized by a pellagra-like light-sensitive rash, cerebellar ataxia, emotional instability, and amino aciduria. 89 Gene mutations in the B 0 AT1 (Slc6a19) neutral amino acid transporter have been identified as a cause of Hartnup's disorder. 90 Despite the lack of mutations of ACE2 and Collectrin in Hartnup's disease, among the known human Hartnup mutations in B 0 AT1, the A69T and R240Q missense mutants were shown to be functionally linked to ACE2 and Collectrin.…”

Section: Ace2 In Hartnup's Disorder and Intestinal Epithelial Immunitymentioning

confidence: 99%

Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases

Kuba

Imai

Penninger

2013

Circ J

176

160

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Section: Ace2 In Hartnup's Disorder and Intestinal Epithelial Immunitymentioning

confidence: 99%

Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases

Kuba

Imai

Penninger

2013

Circ J

176

160

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“…Reduced uptake of neutral amino acids is observed in the rare inherited malabsorption syndrome Hartnup disorder (11). Hartnup disorder is characterized by highly elevated levels of neutral amino acids in the urine and reduced neutral amino acid uptake in the intestine.…”

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confidence: 99%

Impaired Nutrient Signaling and Body Weight Control in a Na+ Neutral Amino Acid Cotransporter (Slc6a19)-deficient Mouse

Bröer

Juelich

Vanslambrouck

et al. 2011

Journal of Biological Chemistry

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Amino acid uptake in the intestine and kidney is mediated by a variety of amino acid transporters. To understand the role of epithelial neutral amino acid uptake in whole body homeostasis, we analyzed mice lacking the apical broad-spectrum neutral (0) amino acid transporter B 0 AT1 (Slc6a19). A general neutral aminoaciduria was observed similar to human Hartnup disorder which is caused by mutations in SLC6A19. Na ؉ -dependent uptake of neutral amino acids into the intestine and renal brushborder membrane vesicles was abolished. No compensatory increase of peptide transport or other neutral amino acid transporters was detected. Mice lacking B 0 AT1 showed a reduced body weight. When adapted to a standard 20% protein diet, B 0 AT1-deficient mice lost body weight rapidly on diets containing 6 or 40% protein. Secretion of insulin in response to food ingestion after fasting was blunted. In the intestine, amino acid signaling to the mammalian target of rapamycin (mTOR) pathway was reduced, whereas the GCN2/ATF4 stress response pathway was activated, indicating amino acid deprivation in epithelial cells. The results demonstrate that epithelial amino acid uptake is essential for optimal growth and body weight regulation.In a typical Western diet humans consume about 80 -100 g of protein per day. Proteins are hydrolyzed by the action of secreted and membrane-bound peptidases into individual amino acids, di-and tripeptides (1). Individual amino acids are taken up by a variety of amino acid transporters, whereas diand tripeptides are absorbed by the peptide transporter PepT1 (SLC15A1) (2). Together this digestive process makes 90 -95% of ingested proteins available to the body. Protein demand is particularly high during growth and development when new proteins are required to build up body mass. In the adult, protein recycling is quite efficient, and only 50 g of protein is needed per day to replace protein lost through urine and feces.The bulk of neutral amino acids is absorbed in the intestine by the neutral amino acid transporter B 0 AT1 (SLC6A19), which is also expressed in the kidney where it mediates reabsorption of neutral amino acids (3). Expression studies in heterologous systems have shown that B 0 AT1 accepts all neutral amino acids with a preference for large neutral amino acids such as branched-chain amino acids and methionine (4, 5). These amino acids are taken up with a K m of about 1 mM, whereas smaller amino acids are taken up with higher K m values. Glycine and proline are poor substrates of B 0 AT1. As a result additional transporters are involved in the uptake of imino acids and glycine, such as PAT1 (SLC36A1), PAT2 (SLC36A2), and IMINO (SLC6A20) (6). Additional transport systems for other neutral amino acids in the kidney and intestine have been proposed; these include a specific intestinal transporter for methionine and phenylalanine (7) and the amino acid antiporter ASCT2 (SLC1A5) as a mediator of small neutral amino acids and glutamine uptake in kidney and intestine (8).Efficient trafficking and sur...

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“…Examples include Hartnup disease (Baron et al 1956), carcinoid syndrome (Castiello & Lynch, 1972;Lehman, 1972;Swain et al 1976), the treatment of tuberculosis with isoniazid (Biehl & Vilter, 1954;Harrison & Feiwel, 1956) and a recently described hereditary pellagra-like condition which did not respond to the administration of nicotinamide (Salih et al 1985). All these findings suggest that under normal conditions tryptophan may be more important as a precursor of the nucleotides than is preformed dietary niacin.…”

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confidence: 99%

The metabolism of high intakes of tryptophan, nicotinamide and nicotinic acid in the rat

McCreanor

Bender

1986

Br J Nutr

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1. The metabolic fate of high dietary intakes of nicotinamide, nicotinic acid and tryptophan, and of acute doses of nicotinamide and nicotinic acid, has been studied in the rat. A new high-pressure liquid chromatography method for measurement of the principal urinary metabolites of niacin is described.2. Administration to rats of a single oral dose of nicotinamide or nicotinic acid (up to 100 mg/kg body-weight), or maintenance for 3 weeks on diets providing 150 mg nicotinamide or nicotinic acid/kg diet, resulted in only a small increase in the liver content of nicotinamide nucleotide coenzymes (NAD and NADP). The quantitative metabolism of nicotinamide and nicotinic acid differed, suggesting that intestinal bacterial deamidation is not the major fate of nicotinamide.3. A high dietary intake of tryptophan (5.9 g/kg diet) led to a considerable increase in liver NAD(P) and also in urinary excretion of niacin metabolites. The results suggest that, as indicated by enzyme kinetic studies (Bender et al. 1982), the utilization of nicotinamide and nicotinic acid for nucleotide synthesis is limited, while there is little or no limitation of NAD(P) synthesis from the tryptophan metabolite quinolinic acid.

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Hereditary Pellagra-Like Skin Rash With Temporary Cerebellar Ataxia, Constant Renal Amino-Aciduria, and Other Bizarre Biochemical Features

Cited by 379 publications

References 10 publications

Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases

Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases

Impaired Nutrient Signaling and Body Weight Control in a Na+ Neutral Amino Acid Cotransporter (Slc6a19)-deficient Mouse

The metabolism of high intakes of tryptophan, nicotinamide and nicotinic acid in the rat

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