Aminoacidurias: Clinical and molecular aspects
2008; Elsevier BV; Volume: 73; Issue: 8 Linguagem: Inglês
10.1038/sj.ki.5002790
ISSN1523-1755
AutoresSimone M. R. Camargo, Detlef Böckenhauer, Robert Kleta,
Tópico(s)Biomedical Research and Pathophysiology
ResumoInherited aminoacidurias are caused by defective amino-acid transport through renal (reabsorption) and in many cases also small intestinal epithelia (absorption). Recently, many of the genes causing this abnormal transport have been molecularly identified. In this review, we summarize the latest findings in the clinical and molecular aspects concerning the principal aminoacidurias, cystinuria, lysinuric protein intolerance, Hartnup disorder, iminoglycinuria, and dicarboxylic aminoaciduria. Signs, symptoms, diagnosis, treatment, causative or candidate genes, functional characterization of the encoded transporters, and animal models are discussed. Inherited aminoacidurias are caused by defective amino-acid transport through renal (reabsorption) and in many cases also small intestinal epithelia (absorption). Recently, many of the genes causing this abnormal transport have been molecularly identified. In this review, we summarize the latest findings in the clinical and molecular aspects concerning the principal aminoacidurias, cystinuria, lysinuric protein intolerance, Hartnup disorder, iminoglycinuria, and dicarboxylic aminoaciduria. Signs, symptoms, diagnosis, treatment, causative or candidate genes, functional characterization of the encoded transporters, and animal models are discussed. Amino-acid transport is vital to life and for many aspects of physiology and pathophysiology. The study of amino-acid transport in epithelial cells, of intestinal or renal proximal tubular origin, and the expression of transporter proteins in heterologous systems, for example, Xenopus laevis oocytes, have been immensely fruitful and provided many clues in the past few years. Furthermore, genetic studies in patients with specific aminoacidurias, and phenotypic observations in knockout mice, have brought several major contributions to our understanding of epithelial amino-acid transport. The recognition of changes in individual amino-acid levels in urine and plasma of patients has further supported research and progress in this field. The association of a disease with an amino-acid transport defect was suggested already a century ago by Sir Archibald Garrod,1.Garrod A.E. The Croonian lectures on inborn errors of metabolism. Lecture III.Lancet. 1908; 172: 142-148Abstract Google Scholar,2.Garrod A.E. The Croonian lectures on inborn errors of metabolism. Lecture IV.Lancet. 1908; 172: 214-220Abstract Scopus (68) Google Scholar the 'father' of metabolic medicine and biochemical genetics. He described cystinuria as cause of nephrolithiasis in his third and fourth Croonian lectures. In the 1950s, a disorder with pellagra-like symptoms associated with 'constant renal aminoaciduria' was named after the affected members of a British family as Hartnup disorder.3.Baron D.N. Dent C.E. Harris H. et al.Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal amino-aciduria, and other bizarre biochemical features.Lancet. 1956; 268: 421-428Abstract Scopus (130) Google Scholar Another new rare disorder was first described shortly thereafter in Finnish patients, who excreted large amounts of dibasic amino acids in the urine, had low plasma concentrations of these amino acids, and severe symptoms including coma. The disorder was called lysinuric protein intolerance (LPI) and was later attributed to an epithelial amino-acid transport defect, even though it resembled much more a classical metabolic disorder with signs and symptoms of elevated blood ammonia.4.Perheentupa J. Visakorpi J.K. Protein intolerance with deficient transport of basic aminoacids. Another inborn error of metabolism.Lancet. 1965; 286: 813-816Abstract Scopus (75) Google Scholar Standard urinary amino-acid screening resulted in the identification of two other asymptomatic aminoacidurias, iminoglycinuria5.Coskun T. Ozalp I. Tokatli A. Iminoglycinuria: a benign type of inherited aminoaciduria.Turk J Pediatr. 1993; 35: 121-125PubMed Google Scholar, 6.Goodman S.I. McIntyre Jr, C.A. O'Brien D. Impaired intestinal transport of proline in a patient with familial iminoaciduria.J Pediatr. 1967; 71: 246-249Abstract Full Text PDF PubMed Scopus (14) Google Scholar, 7.Rosenberg L.E. Durant J.L. Elsas L.J. Familial iminoglycinuria. An inborn error of renal tubular transport.N Engl J Med. 1968; 278: 1407-1413Crossref PubMed Scopus (24) Google Scholar and dicarboxylic aminoaciduria.8.Melancon S.B. Dallaire L. Lemieux B. et al.Dicarboxylic aminoaciduria: an inborn error of amino acid conservation.J Pediatr. 1977; 91: 422-427Abstract Full Text PDF PubMed Scopus (34) Google Scholar,9.Swarna M. Rao D.N. Reddy P.P. Dicarboxylic aminoaciduria associated with mental retardation.Hum Genet. 1989; 82: 299-300Crossref PubMed Scopus (20) Google Scholar In principal, clinical consequences in specific aminoacidurias can arise from either the deficiency of particular amino acids (lack of absorption in the intestine and urinary loss) or the precipitation of certain amino acids (cystine) in the urine. The study of aminoacidurias was greatly facilitated by the advent of paper chromatography10.Dent C.E. A study of the behaviour of some sixty amino-acids and other ninhydrin-reacting substances on phenol-'collidine' filter-paper chromatograms, with notes as to the occurrence of some of them in biological fluids.Biochem J. 1948; 43: 169-180Crossref Scopus (66) Google Scholar and then ion exchange chromatography in the 1950s.11.Spackman D.H. Stein W.H. Moore S. Automatic recording apparatus for use in the chromatography of amino acids.Anal Chem. 1958; 30: 1190-1206Crossref Scopus (6501) Google Scholar The latter method can reliably detect and quantify minute amounts of individual amino acids in body fluids like plasma and urine, or even in subcellular compartments. The individual amino acids are separated based on their distinct physicochemical properties by high-pressure liquid chromatography in specialized columns (packed with cation exchange resins). The principle of the most commonly used assay is the formation of colored compounds from the reaction of amino or imino acids with ninhydrin. The amount of light absorbed at two wavelengths, 570 nm (amino acids) and 440 nm (imino acids), is proportional to the quantity of amino acids present. Even though amino acids can nowadays be detected by different and even more sophisticated methods, ion exchange chromatography has remained the method of choice for clinical practice. The pathophysiology of aminoacidurias teaches us a lot about epithelial transport physiology. In intestinal and proximal kidney tubule epithelia, specific amino-acid transporters, located on both the luminal and basolateral membranes, together perform an 'uphill' transcellular transport, that is, against the concentration gradient back into the extracellular blood compartment. This net transport is very efficient, and in the renal proximal tubule up to 99% of free amino acids, filtered through the glomerulus, are reabsorbed and thus retained by the organism. Initially, amino-acid transport types were classified according to specificity and sodium dependence described as systems, a classification that is still used by physiologists. Examples of such systems are, for instance, B0 (broad selectivity sodium-dependent neutral amino-acid transport), b0,+ (broad selectivity sodium-independent neutral and basic amino-acid transport), y+L (sodium-independent basic amino-acid transport), and XAG (sodium-dependent acidic amino-acid transport).12.Christensen H.N. Role of amino acid transport and countertransport in nutrition and metabolism.Physiol Rev. 1990; 70: 43-77Crossref PubMed Scopus (923) Google Scholar With the increasing number of molecularly identified transporters, a more homogeneous nomenclature was necessary. The solute carrier families (SLC) nomenclature, based on gene homology, was introduced by the Human Genome Organization (HUGO). Unfortunately, some confusion persists, as this system is based on homology rather than on function. In addition, protein names are not necessarily following specific rules. For the purpose of this review, the specific aminoacidurias identified so far (see Table 1) were classified by the chemical properties of the amino acids abnormally excreted (that is, neutral, basic (cationic), acidic (anionic), or imino acids). Amino acids mentioned are L-forms unless specified otherwise. Gene names according to HUGO are mentioned first followed by agreed and commonly used protein names, for example, SLC6A19 (B0AT1).Table 1Aminoacidurias genetically elucidated in humanAminoaciduriaGeneHUGOProteinChromosomeHallmark (elevation of individual AA in urine)Cystinuria ASLC3A1Solute carrier family 3 (cystine, dibasic, and neutral amino-acid transporters, activator of cystine, dibasic, and neutral amino-acid transport), member 1rBAT2p21Cystine, lysine, arginine, ornithineCystinuria BSLC7A9Solute carrier family 7 (cationic amino-acid transporter, y+ system), member 9b0,+AT19q13.11Cystine, lysine, arginine, ornithineCystinuria ABSLC3A1/SLC7A9Cystine, lysine, arginine, ornithineLysinuric protein intoleranceSLC7A7Solute carrier family 7 (cationic amino-acid transporter, y+ system), member 7y+LAT114q11.2Lysine, arginine, ornithineHartnup disorderSLC6A19Solute carrier family 6 (neutral amino-acid transporter), member 19B0AT15p15.33Neutral amino acidsIminoglycinuria???Proline, hydroxyproline, glycineDicarboxylic aminoaciduria???Aspartate, glutamateHUGO, Human Genome Organization; NCBI, National Center for Biotechnology Information.According to HUGO (http://www.genenames.org) and NCBI build 36.2.? signifies unknown. Open table in a new tab HUGO, Human Genome Organization; NCBI, National Center for Biotechnology Information. According to HUGO (http://www.genenames.org) and NCBI build 36.2. ? signifies unknown. Patients with cystinuria often present with nephro- or urolithiasis at almost at any age with a clear preference in childhood due to elevated urinary cystine. Kidney stones are radio opaque, although less than calcium-containing ones, and easily diagnosed by ultrasound examinations. Stones often form in the bladder and the presence of a bladder stone in a child should always prompt consideration of cystinuria. Early diagnosis is important, as it allows prevention or diminution of kidney stones. Diagnostically, urinary levels of dibasic amino acids lysine, arginine, and ornithine, and most prominently, of cystine are constantly elevated (for example, cystine up to 50 times normal). Plasma levels of these amino acids in general are at the lower end of the normal range. The clinical problems arise only from the elevated urinary cystine, which precipitates within the urinary tract and forms cystine stones due its low solubility. Urine microscopy reveals characteristic and pathognomonic hexagonal crystals. The cyanide–nitroprusside urinary test is also used, but it is not considered specific. Treatment overall is nonspecific and consists mostly of a high fluid intake to keep the urinary cystine below the solubility threshold of about 1000 μmol l−1 (at pH S2>S3) and enterocytes (jejunal and ileal), but in contrast to cystinuria to the basolateral membranes.21.Dave M.H. Schulz N. Zecevic M. et al.Expression of heteromeric amino acid transporters along the murine intestine.J Physiol. 2004; 558: 597-610Crossref PubMed Scopus (99) Google Scholar,38.Bauch C. Forster N. Loffing-Cueni D. et al.Functional cooperation of epithelial heteromeric amino acid transporters expressed in Madin–Darby canine kidney cells.J Biol Chem. 2003; 278: 1316-1322Crossref PubMed Scopus (65) Google ScholarSLC3A2 (4F2hc), the heavy subunit of the basolateral basic amino-acid transporter, functions as a chaperone, assisting in the sorting of the light subunit SLC7A7 (y+LAT1) to the plasma membrane.36.Pfeiffer R. Rossier G. Spindler B. et al.Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family.EMBO J. 1999; 18: 49-57Crossref PubMed Scopus (228) Google Scholar,39.Kleemola M. Toivonen M. Mykkanen J. et al.Heterodimerization of y(+)LAT-1 and 4F2hc visualized by acceptor photobleaching FRET microscopy.Biochim Biophys Acta. 2007; 1768: 2345-2354Crossref PubMed Scopus (8) Google Scholar When overexpressed in an epithelial cell model (MDCK cells), in the absence of SLC3A2 (4F2hc), only a small fraction of SLC7A7 (y+LAT1) appeared at the basolateral surface (putatively associated with endogenous SLC3A2 (4F2hc)). Whereas overexpression of both the heavy and light subunits resulted in their colocalization in the basolateral membrane.38.Bauch C. Forster N. Loffing-Cueni D. et al.Functional cooperation of epithelial heteromeric amino acid transporters expressed in Madin–Darby canine kidney cells.J Biol Chem. 2003; 278: 1316-1322Crossref PubMed Scopus (65) Google Scholar This heterodimeric transporter effluxes, with high affinity (micromolar range), dibasic amino acids in exchange for neutral amino acids and Na+36.Pfeiffer R. Rossier G. Spindler B. et al.Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family.EMBO J. 1999; 18: 49-57Crossref PubMed Scopus (228) Google Scholar resulting together with the action of b0,+AT (SLC7A9) and its subunit rBAT (SLC3A1) in the net reabsorption of dibasic amino acids (see Figure 1). The significance of the clinical picture in LPI can be explained by a more severe loss of dibasic amino acids in comparison to cystinuria leading to an inefficient urea cycle resulting in hyperammonemia. Obviously, a defect in the basolateral export of dibasic amino acids (as in LPI) has more severe consequences than a defect in the luminal membrane (as in cystinuria). This is, in particular, attributed to the fact that a large fraction of the nutritional amino acids, inclusively dibasic amino acids, are (re)absorbed as di- and tripeptides, which are then hydrolyzed intracellularly before they are transported out of the cell through the basolateral membrane. Some of the unique immunological features of this disease are most probably related to the expression profile of SLC7A7 (y+LAT1), which is much broader than that of SLC3A1/SLC7A9 (rBAT/b0,+AT).29.Broer S. Lysinuric protein intolerance: one gene, many problems.Am J Physiol Cell Physiol. 2007; 293: C540-C541Crossref PubMed Scopus (22) Google Scholar A mouse model, generated by inactivation of Slc7a7, displayed intrauterine growth retardation with only two animals surviving the neonatal period. These two surviving knockout mice were maintained on a low-protein diet and citrulline supplementation, and when introduced to a high-protein diet displayed a metabolic dysfunction almost identical to that observed in the human syndrome.40.Sperandeo M.P. Annunziata P. Bozzato A. et al.Slc7a7 disruption causes fetal growth retardation by downregulating Igf1 in the mouse model of lysinuric protein intolerance.Am J Physiol Cell Physiol. 2007; 293: C191-C198Crossref PubMed Scopus (33) Google Scholar First recognized in the 1950s in London as a defect of neutral amino-acid transport, Hartnup disorder became an example of how diet can unveil signs and symptoms of a multifaceted disease. The protein-restricted diet imposed to the population (World War II, postwar) revealed the defective (re)absorption of amino acids characteristic of the Hartnup disorder. Patients can present with signs and symptoms of pellagra (including light-sensitive dermatitis), intermittent cerebellar ataxia, and psychosis-like symptoms. These symptoms, generally considered the result of niacin deficiency, are thought to be caused by deficiency of tryptophan, as this is a precursor of niacin and serotonin. Diagnostically, elevated urinary neutral amino acids are the first indication of the disorder. The intestinal malabsorption of tryptophan can be additionally tested by an indican–indole test, although this is rarely used and not readily available. The neutral aminoaciduria has to be differentiated from generalized aminoaciduria, which would be an obligate diagnostic hallmark of a renal Fanconi syndrome. The most common cause of the renal Fanconi syndrome in childhood is cystinosis, a treatable lysosomal storage disorder. Currently, patients from 'protein supersaturated' countries are often recognized only by newborn screening programs, as they are asymptomatic. The question remains whether these patients should or need to be treated at all. Patients with pellagra-like symptoms are treated with niacin oral replacement, which reverses the clinical features of the disorder. The incidence of Hartnup disorder is estimated to be in the range of 1:15 000 births. Mutations in SLC6A19, encoding the neutral amino-acid transporter B0AT1, mediating
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