Hartnup Disorder

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Introduction to Hartnup Disorder

Hartnup disorder is an autosomal recessive disorder that was first described in 1956 in the Hartnup family in London. The originally characterized patients exhibited a renal aminoaciduria of neutral amino acids associated with a pellagra-like skin rash and episodes of cerebellar ataxia. Indeed, in the original publication documenting this disorder the authors described the clinical features as: "hereditary pellegra-like skin rash with temporary cerebellar ataxia, constant renal aminoaciduria and other bizarre biochemical features". Since its initial characterization Hartnup disorder has been found to have a frequency of occurence on the order of 1:30,000 in European populations. However, although the original patient presented with the symptoms described, many individuals with the disorder remain nearly asymptomatic with skin rashes and diarrhea in infancy being the most severe manmifestations. Regardless of the broad range of symptom presentation the hallmark of Hartnup disorder is aminoaciduria. Almost all affected individuals are correctly diagnosed thorugh urine analysis.

Hartnup disorder is caused by a defect in neutral amino acid transport in the apical brush border membranes of the small intestine and in kidney proximal tubules. The transporter is a member of the solute carrier family, specifically the SLC6A19 transporter. SLC6A19 is also known as the system B(0) [also written as B0] neutral amino acid transporter 1 [B(0)AT1 or B0AT1]. The B refers to a broad specificity transporter, the 0 denotes the transporter as one for neutral amino acids, and the supercripting of the 0 denotes that the transporter is a Na+-dependent transporter. The SLC6A19 transporter prefers large aliphatic neutral amino acids. Of significance to overall amino acid homeostasis is the fact that the SCL6A19 encoded transporter transports eight of the ten essential amino acids, namely leucine, isoleucine, valine, methionine, phenylalanine, tryptophan, threonine, and hisitidine. Of significance, specifically to Hartnup disorder is that SLC6A19 is the major transporter of tryptophan in the intestines and its lack, in Hartnup disorder, is key to the pathology of the disorder.

The SLC6A19 gene is located on chromosome 5p15.33 and is composed of 12 exons that encode a 635 amino acid protein. Mutations in the SLC6A19 gene that result in Hartnup disorder include missense mutations, nonsense mutations, deletions, and splice site mutations. To date a total of 21 different mutations have been identified with missense mutations representing the bulk of the identified mutations. Within Europeans the most frequent mutation is a missense mutation converting an Asp codon at amino acid 173 to an Asn, designated the D173N mutation.

Clinical Features of Hartnup Disease

Symptoms of Hartnup disorder may begin in infancy or early childhood, but sometimes they begin as late as early adulthood. Symptoms may be triggered by sunlight, fever, drugs, or emotional or physical stress. Most symptoms occur sporadically and are caused by a deficiency of the niacin (vitamin B3) derived enzyme cofactors, NAD+ and NADP+. When Hartnup disorder manifests during infancy the symptoms can be variable in clinical presentation. These symptoms include failure to thrive, photosensitivity, intermittent ataxia, nystagmus and tremor. Since tryptophan is also required for the synthesis of melatonin, it is believed that skin sensitivity to sunlight is exerted, in part, by a lack or reduction in melatonin synthesis. In addition to the regulation of circadian rhythm melatonin has been shown to exert protective effects in the skin as well as being a regulator of skin structure and function. The cerebellar ataxia associated with Hartnup disorder is likely du to reduced synthesis of serotonin which is derived from tryptophan.

The lack of intestinal tryptophan transport is responsible for most, if not all, clinical phenotypes of Hartnup disorder. The pellagra-like skin rash seen on sun-exposed areas of skin in Hartnup disorder patients is most likely the result of nicotinamide adenine dinucleotide (NAD+ and NADP+) deficiency due to a lack of tryptophan which is a precursor for its synthesis. The significance of tryptophan to the overall NAD+ and NADP+ pool can be clearly demonstrated in Hartnup disorder given that the symptoms of skin rash, in these patients, resolve upon niacin (vitamin B3) supplementation.

Variability in presentation of Hartnup disorder symptoms arises due to both dietary influences and the fact that other proteins associate with, and affect the activity of, SLC6A19. As to dietary effects, persons who consume a high protein diet tend to be the most asyptomatic due to the contribution of intestinal peptide transport to the overall absorption of tryptophan. Indeed, most patients with Hartnup disorder can remain asymptomatic on a high protein diet due to intestinal peptide absorption via the actions of the peptide transporter, PepT1. In comparison, individuals who consume high carbohydrate, low protein diets are more likely to exhibit the most severe manifestations of Hartnup disorder.

The SLC6A19 transporter has been shown to require the activity of another protein for proper trafficking to the brush border membranes of renal tubular cells. This fact was discovered in a mutant mouse that excreted large amounts of neutral amino acids and was found to harbor a deficiency in the protein commonly identified as collectrin. These mutant mice have a near complete lack of SLC6A19 protein in the bruch border membranes of renal tubular cells. Collectrin is a type I transmembrane protein that shares homology with the C-terminal domain of angiotensin converting enzyme 2 (ACE2). Although sharing significant homology with ACE2, collectrin lacks the catalytic domain, and therefore, does not posses proteolytic activity. Collectrin was so-called because of its function in ciliated cells in the collecting ducts of the kidney. Collectrin is involved in the processes of vesicular trafficking via its interaction with SNARE complexes. One important function for collectrin is in the secretion of insulin from pancreatic β-cells. The collectrin protein is encoded by the TMEM27 (transmembrane protein 27) gene. Expression of the TMEM27 gene is highest in renal collecting duct cells, renal proximal tubule cells, and pancreatic β-cells but it not expressed in the intestines which explains why collectrin deficient mice only exhibit neutral amino aciduria. Expression of the TMEM27 gene is regulated by hepatocyte nuclear factor 1α (HNF-1α; encoded by the HNF1A gene) which explains the neutral aminoaciduria that is associated with the inherited form of diabetes mellitus termed MODY3 (maturity onset diabetes of the young type 3) which results from mutations in the HNF1A gene. Within the intestines the SLC6A19 encoded protein is found associated with ACE2. In the intestines ACE2 is involved in peptde digestion and as such feed neutral amino acids to SLC6A19. In the vasculature ACE2 cleaves angiotensin II to angiotensin 1-7, thereby inactivating angiotensin II. Some, but not all, mutations in the SLC6A19 gene result in proteins that do not effectively interact with ACE2 in the intestines accounting for some of the phenotypic variations seen in Hartnup disorder.












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Michael W King, PhD | © 1996–2017 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org

Last modified: June 23, 2017