Disorder Of Amino Acid Transport Research Articles

Hyperammonemia in a Child Presenting with Growth Delay, Short Stature, and Diarrhea

A 5-year-old male child was referred to the metabolism clinic with a history of failure to thrive, chronic intermittent emesis, diarrhea, seizures, hypotonia, and growth hormone deficiency. He was also noted to experience frequent falling episodes. Routine biochemistry testing revealed increased plasma ammonia concentration at 184 μmol/L (reference interval, 16–47) and lactate dehydrogenase concentration at 445 U/L (reference interval, 110–295). Plasma free and total carnitine concentrations were decreased at 5 μmol/L (reference interval, 26–60) and 17.1 μmol/L (reference interval, 32–84), respectively. Orotic acid excretion in urine was also markedly increased at >80 mmol/mol creatinine (reference interval, 0.2–1.5). Plasma insulin-like growth factor-I (IGF-I)4 concentration was also decreased at <25 ng/mL (reference interval, 50–286). Paired plasma and urine specimens were collected for amino acid analysis using ultraperformance liquid chromatography. The results are shown in Table 1. View this table: Table 1. Amino acid analysis of paired plasma and urine. This patient has lysinuric protein intolerance (LPI), an autosomal recessive disorder of amino acid transport, caused by mutations in the solute carrier family 7, member 7 ( SLC7A7 ) gene (1, 2, 3). Although the worldwide incidence is not known, LPI is estimated to occur in approximately 1 in 60000 newborns in Finland and Japan (2). The SLC7A7 gene product is the …

Twenty-Four Novel Mutations Identified in a Cohort of 85 Patients by Direct Sequencing of the SLC3A1 and SLC7A9 Cystinuria Genes

Mutations in the SLC3A1 and SLC7A9 genes cause cystinuria (OMIM 220100), an autosomal recessive disorder of amino acid transport and reabsorption in the proximal renal tubule and in the epithelial cells of the gastrointestinal tract. In an attempt to characterize the molecular defect in the SLC3A1 and SLC7A9 genes, we analyzed a cohort of 85 unrelated subjects clinically diagnosed as affected by cystinuria on the basis of stone formation, prevalently of Italian and Greek origin. Analysis of all coding region and exon-intron junctions of the SLC3A1 and SLC7A9 genes by using direct sequencing method allowed us to identify 62 different mutations in 83 out of 85 patients accounting for 90.5% of all affected chromosomes. Twenty-four out of 62 are novel mutations, 9 in SLC3A1 and 15 in SLC7A9. In conclusion, this report expands the spectrum of SLC3A1 and SLC7A9 mutations and confirms the heterogeneity of this disorder.

Introductory Speech for Charles Scriver

Introductory Speech for Charles Scriver

Cystinuria type I: Identification of eight new mutations in SLC3A1

Cystinuria is a heritable disorder of amino acid transport characterized by the defective transport of cystine and the dibasic amino acids through the brush border epithelial cells of the renal tubule and intestine tract. Three types of cystinuria (I, II, and III) have been described based on the urinary excretion of cystine and dibasic amino acids in obligate heterozygotes. The SLC3A1 gene coding for an amino acid transporter named rBAT is responsible for type I cystinuria, whereas the SLC7A9 gene coding for a subunit (b0,+AT) of rBAT is involved in determining non-type I (types II and III) cystinuria. The SLC3A1 gene sequence was investigated in a sample of seven type I/type I, three type I/non-type I, six type I/untyped, and four untyped unrelated cystinuric patients by RNA single-strand conformation polymorphism (RNA-SSCP). Eight new point mutations (S168X, 765+1G>T, 766-2A>G, R452Q, Y461X, S547W, L564F, and C673W) and seven previously reported mutations were detected. These new mutations increase the number of mutated alleles so far characterized in SLC3A1 to 62. We have found SLC3A1 mutations in 0.739 of the type I chromosomes studied. The relatively high proportion of uncharacterized type I chromosomes suggests either that there may be mutations not yet found in SLC3A1 or that many of the assigned type I chromosomes in mixed type I/non-type I patients may have mutations in SLC7A9. If the hypothesis is excluded in the future, we believe that a third gene may be involved in cystinuria.

Genomic Structure and Organization of the HumanrBATGene (SLC3A1)

Cystinuria is an autosomal recessive disorder of amino acid transport, manifesting as three phenotypes (I, II, and III). An amino acid transport gene,rBAT,is responsible for cystinuria. Mutation and linkage analyses have demonstrated the disease to be heterogeneous, withrBATbeing the defective gene in type I cystinuria. The genomic structure of the humanrBATgene (HGMW-approved symbol SLC 3A1) has been established via two strategies: (i) construction of two different genomic libraries by subcloning the MegaYAC921B6 (CEPH), containingrBAT,in Lambda ZAP and screening usingrBATcDNA and different PCR products; and (ii) generation and sequencing of genomic fragments by long PCR usingrBATcDNA-derived primers. TherBATgene spans approximately 45 kb and consists of 10 exons. The introns range from 500 to 13,000 bp. All splice sites conform to the GT/AG rule. The promoter region has been further analyzed, and a predicted TATA box 98 bp upstream of the first coding ATG was identified. In addition anAlurepeat has been detected 72 bp upstream of the predicted TATA box.

Assignment of the gene responsible for cystinuria (rBAT) and of markers D2S119 and D2S177 to 2p16 by fluorescence in situ hybridization

We have established rBAT (named as SLC3A1 in the Genome Data Base) as a gene responsible for cystinuria, a heritable disorder of amino acid transport. The cystinuria locus has been mapped by linkage between microsatellite markers D2S119 and D2S177. Fluorescene in situ hybridization (FISH) either with Alu-polymerasechain-reaction (PCR)-amplified sequences of a yeast artificial chromosome (YAC) containing the rBAT gene or with rBAT-specific PCR-amplified genomic fragments, and chromosome G-banding have cytogenetically mapped rBAT to 2p16.3. In order to correlate the physical and genetic information on cystinuria, we have performed FISH with combinations of Alu-PCR- amplified sequences from YACs containing rBAT or the D2S119 and D2S177 loci. In all cases, a fused signal is obtained that demonstrates their close physical location; this allows the assignment of rBAT, cystinuria and their linked markers, D2S119 and D2S177, to 2p16.

Assignment of the gene responsible for cystinuria (rBAT) and of markers D2S119 and D2S177 to 2p16 by fluorescence in situ hybridization

We have established rBAT (named as SLC3A1 in the Genome Data Base) as a gene responsible for cystinuria, a heritable disorder of amino acid transport. The cystinuria locus has been mapped by linkage between microsatellite markers D2S119 and D2S177. Fluorescence in situ hybridization (FISH) either with Alu-polymerase-chain-reaction (PCR)-amplified sequences of a yeast artificial chromosome (YAC) containing the rBAT gene or with rBAT-specific PCR-amplified genomic fragments, and chromosome G-banding have cytogenetically mapped rBAT to 2p16.3. In order to correlate the physical and genetic information on cystinuria, we have performed FISH with combinations of Alu-PCR-amplified sequences from YACs containing rBAT or the D2S119 and D2S177 loci. In all cases, a fused signal is obtained that demonstrates their close physical location; this allows the assignment of rBAT, cystinuria and their linked markers, D2S119 and D2S177, to 2p16.

Localization of a gene causing cystinuria to chromosome 2p.

Cystinuria is an autosomal recessive disorder of amino acid transport. It is a common hereditary cause of kidney stones worldwide, and is associated with significant morbidity. In 17 affected families, we found linkage between cystinuria and three chromosome 2p markers. Maximal two-point lod scores between cystinuria and D2S119, D2S391 and D2S288 were 8.23 (theta = 0.07), 3.73 (theta = 0.15) and 3.03 (theta = 0.12), respectively. Analysis of recombinants and multipoint linkage data indicated that the most likely order is cen-D2S391-D2S119-cystinuria-D2S177-tel. We also observed high rates of homozygosity for markers in this chromosomal region among 11 affected offspring of consanguineous marriages. Based on its map position and function, the recently cloned SLC3A1 amino acid transporter gene is a primary candidate gene for this disease.

Renal amino acid transport: cellular and molecular events from clearance studies to frog eggs.

This article reviews recent advances in the mechanisms of renal amino acid transport. Renal amino acid transport is necessary to efficiently reclaim approximately 450 mmol amino acids from the glomerular ultrafiltrate each day in man. In general, individual amino acids are transported across the epithelial membrane of the proximal tubule by a sodium (Na+) dependent mechanism. This cotransport process utilizes the energy of the Na+ gradient to enter the cell. The amino acid then exits the basolateral surface and Na+ is pumped out by the Na(+)-K(+)-ATPase located in the basolateral membrane. In addition to the cellular accumulation of amino acids across the luminal membrane, these compounds may be taken up by the cell from the basolateral surface. Most amino acids are transported both individually and in a series of seven group specific processes. Human disorders of amino acid transport have been described for six of the seven transport systems. The process of ontogeny of amino acid accumulation by the proximal tubule is a complex one and will be further discussed in this review. A number of factors including pH, ion dependency, electrogenicity of transport process, as well as a variety of hormonal factors, may contribute to the regulation of amino acid transport. Gene expression of several amino acid transporters has been successfully performed using the oocyte of the frog Xenopus laevis. Using this system, a number of transporters have been cloned. Such a strategy will permit the cloning of virtually all transporter molecules, and thus we can anticipate the elucidation of the structure of the transporters. However, for a comprehensive understanding of cytoskeletal interactions protein phosphorylation and phospholipid domains and their linkage to the primary structure of the transporter need to be studied. The future for research in this area is indeed a bright one.

Cystinuria

Cystinuria is an inherited disorder of amino acid transport characterized by excessive excretion of cystine, lysine, arginine, and ornithine. Urolithiasis is caused by the relative insolubility of cystine in the urine. Symptoms often occur in childhood or early adult life, but cystinuria may become clinically evident at any age. Repeated stone formation is typical. An integrated program of medical and surgical management is important in achieving a favorable long-term outcome.

Disorders of amino acid transport.

Conference Article| December 01 1983 Disorders of amino acid transport S. SEGAL S. SEGAL 1Division of Biochemical Development and Molecular Diseases, Children's Hospital of Philadelphia, and Departments of Pediatrics and Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, U.S.A. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1983) 11 (6): 633–634. https://doi.org/10.1042/bst0110633 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation S. SEGAL; Disorders of amino acid transport. Biochem Soc Trans 1 December 1983; 11 (6): 633–634. doi: https://doi.org/10.1042/bst0110633 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1983 Biochemical Society1983 Article PDF first page preview Close Modal You do not currently have access to this content.

Oral administration of urea cycle intermediates in lysinuric protein intolerance: Effect on plasma and urinary arginine and ornithine

In lysinuric protein intolerance, an autosomal recessive disorder of amino acid transport, oral citrulline increases the plasma concentration of urea cycle intermediates more than does oral arginine or ornithine. The clinical improvement suggests that citrulline affords the best means of correcting the ornithinopenic malfunction of the urea cycle.

9Diagnosis and management of inherited aminoacidopathies in the newborn and the unborn

Disorders of amino acid metabolism have played a prominent role in the evolution of our concepts of inherited metabolic diseases since the inception of this field. Three of the four disorders which led Archibald Garrod (1908) to his seminal concepts of 'inborn errors of metabolism' involved amino acids (alcaptonuria, cystinuria, and albinism). Another aminoacidopathy, phenylketonuria, claims historical import for several reasons: it was the second inborn error for which a specific enzymatic deficiency was identified in vitro; it was the first disease for which mass neonatal screening was ordered by law; and it was the first enzymopathy documented to respond to specific dietary restriction. During the past thirty years, more than 80 different disorders of amino acid transport and catabolism have been described, and the logarithmic increase in newly recognised conditions continues (Scriver and Rosenberg, 1973). Individually, each of the aminoacidopathies is rare, but collectively they affect about 1/1000 humans in whom they cause a very considerable morbidity and mortality (Levy, Shih and MacCready, 1972). The inherited aminoacidopathies provide a glimpse of the richness of the fabric of human mutations, or 'nature's experiments'. Mass screening for disorders such as PKU and homocystinuria which cause delayed clinical manifestations will not be discussed in this chapter as it is dealt with elsewhere in this volume (see page 153 ff.) and also because this matter has been reviewed extensively in the past (Scriver and Rosenberg, 1973); nor will the harmless aminoacidopathies (i.e., iminoglycinuria, cystathioninuria) be considered. Rather, it is the signs, symptoms, diagnostic approach, and management of children with those disorders of amino acid metabolism which lead to acute, life-threatening consequences in the first days or weeks of life which will be surveyed. For specific details of individual disorders, the reader is referred to recent articles, chapters or books by O'Brien and Goodman (1970), Frimpter (1973), Scriver and Rosenberg (1973) and Rosenberg and Scriver (1974).

Disorders of intestinal transport of amino acids.

AMINO acids, the primary structural units of proteins, are transported against electrical and concentration gradients across the epithelial cells of the tubule and the intestine and across the plasma membranes of most cells. In recent years it has become evident that specific amino acid transport mechanisms in the intestine may be comparable to those in the tubule, and may be under the same genetic control. Inherited diseases which directly or indirectly affect these mechanisms are referred to as disorders of amino acid transport. Such disorders were historically discovered as renal amino acidurias. (Renal amino are a group of disorders in which the capacity of the tubules to reabsorb amino acids is reduced [low threshold]. They must be differentiated from two groups of disorders in which known extrarenal enzyme defects produce amino acidurias but in which there are no transport abnormalities. In the first group an

DISORDERS OF AMINO ACID TRANSPORT.

Excerpt Within recent years authorities on cystinuria have concluded that renal clearance evidence has clarified the pathogenesis of this hereditary disease (1, 2). The National Institutes of Healt...

DISORDERS OF AMINO-ACID TRANSPORT.

DISORDERS OF AMINO-ACID TRANSPORT.