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Dibasic aminoaciduria 2

Lysinuric protein intolerance (LPI), also named hyperdibasic aminoaciduria type 2 or familial protein intolerance (MIM 222700), is an autosomal recessive disorder of diamino acid transport. About 100 patients have been reported, almost half of them of Finnish origin. more...

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In LPI, urinary excretion of cationic amino acids (ornithine, arginine and lysine) is increased and these amino acids are poorly absorbed from the intestine. Therefore, their plasma concentrations are low and their body pools become depleted. Deficiency of arginine and ornithine restricts the function of the urea cycle and leads to hyperammonemia after protein-rich meals. Deficiency of lysine may play a major role in the skeletal and immunological abnormalities observed in LPI patients.


The diagnosis is based on the biochemical findings (increased concentrations of lysine, arginine and ornithine in urine and low concentrations of these amino acids in plasma, elevation of urinary orotic acid excretion after protein-rich meals, and inappropriately high concentrations of serum ferritin and lactate dehydrogenase isoenzymes) and the screening of known mutations of the causative gene from a DNA sample.


Infants with LPI are usually symptom-free when breastfed because of the low protein concentration in human milk, but develop vomiting and diarrhea after weaning. The patients show failure to thrive, poor appetite, growth retardation, enlarged liver and spleen, prominent osteoporosis, delayed bone age and spontaneous protein aversion. Forced feeding of protein may lead to convulsions and coma. Mental development is normal if prolonged episode of hyperammonemia can be avoided. Some patients develop severe pulmonary and renal complications.

Treatment and prognosis

Treatment of LPI consists of protein-restricted diet and supplementation with oral citrulline. Citrulline is a neutral amino acid that improves the function of the urea cycle and allows sufficient protein intake without hyperammonemia. Under proper dietary control and supplementation, the majority of the LPI patients are able to have a nearly normal life.


Simell, O et al: Lysinuric protein intolerance. Am J Med. 1975 Aug;59(2):229-40, .


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Is the broad range amino acid transporter which is induced b
From Nutrition Reviews, 6/1/94

Forty-three years ago Dent and Rose(1) showed that lysine and arginine along with cystine (ornithine was added later) are lost into the urine in human cystinuria. It is a curious reflection of a major change in viewpoint that these authors excluded cystinuria as an inborn error of metabolism. They viewed their result as negating the association proposed by the title, Amino acid metabolism in cystinuria, and as proving instead that the defect producing cystinuria was not metabolic. Today, however, we would be hard pressed to discuss metabolism without a discussion of the contributions of biological membranes to metabolic processes.

Although the renal defect came thus to be applied particularly to amino acids, the renal resorption of these amino acids has frequently been shown susceptible to inhibition by various dipolar(2-5) (neutral) amino acids. According to Vokl and Silbernagl(2) the range of resorption intensity is as follows: alanine

Helpful new characterizations have become available for the transport systems that appear to be involved in the observed interactions.(4,6) However, a full understanding of the genetic defect of cystinuria appears now likely to come from the ongoing expression cloning of the responsible gene. Bertran et al.,(7-8) and later, Furriols et al.(9) has found that a renal cDNA isolate in both rats and humans induces in Xenopus oocytes a transporter for L-cystine whose activity is shared not only among the cationic amino acids but also with various dipolar amino acids. This broad scope, although undoubtedly of ultimate biological importance and technical advantage in identifying the transporter defect, does not necessarily imply that nutritionally important losses of dipolar amino acids occur in cystinuria. These minor losses are probably compensated for by other parallel transport systems.

The range of the amino acids transported and the sodium-ion independence of the transport led to a provisional designation of the induced system as a "system b sup o,+ -like" transporter. This term refers to these two aspects, which are seen in a transport system described by Van Winkle et al.(10,11) for the mouse blastocyst. Note that an epithelial character can be ascribed to the blastocyst, and that the defect of cystinuria does apply to epithelial amino acid absorption in the intestine as well as to resorption in the kidney, an aspect that establishes the nutritional relevance of this development.

Concurrently, Wells and Hediger(12) have isolated a rat kidney cDNA designated as D2, which also causes Xenopus oocytes to take up cystine and the more distinctly cationic amino acids prominently involved in cystinuria. But uptake of 7 of 11 dipolar amino acids tested was also stimulated. cDNA of the same character was also found in the intestine, but not in lung or skeletal muscle. Mutual inhibition of the transport produced occurred between the transported diamino and monoamino acids. An antisense oligonucleotide sharply decreased (14)C-cystine uptake by the treated oocytes.

The cDNA studied concurrently by Bertran et al.(7) was provisionally designated rBAT to indicate that the amino acid scope shown by the transporter induced identifies it with a transport of the b sup 0,+ -type, rather than of the system L or y+ type. By delaying any extension of the naming of the transporter per se and by appending the letter "r" to their designation for this cDNA, Palacin and his associates(8) have maintained a reserved position as to whether this cDNA causes the de novo expression of the transporter itself, or perhaps instead of an inducer or regulator of a b sup 0,+ transporter endogenous to the oocyte. This precaution arises from the growing recognition that increases in the activity of a transporter can arise from an inducement or stimulation of an endogenous Xenopus transporter, rather than from a de novo expression of an exogenous transporter. Van Winkle(11) has reviewed this problem in light of the various transporters he and his associates have shown endogenous to oocytes.(10)

Note that a similar precaution was taken concurrently by Wells and Hediger(12) by designating their cDNA isolate as D2. The merit of this reservation was established by their remarkable finding of only one potentially membrane-spanning stretch in the amino acid sequence of the protein obtained by expression-cloning. This result shows that their protein does not belong in recognized transporter families, although it does not entirely exclude its participation in some other way in transport. Its structure resembles more that of the glucosidases, so that it might be an enzyme involved in carbohydrate metabolism. This puzzling difference between the proteins obtained by the two laboratories recalls the pioneer isolation by expression-cloning of a protein of related origin by Tate et al.(13) Although originally considered for the role of a system L transporter, the authors subsequently found this protein to transport cationic as well as dipolar amino acids. Their protein showed, at the most, only four potentially membrane-spanning domains, so the identity of its role with either of the other two proteins appears unconfirmed.

A new paper from Furriols et al.(9) shows that the protein product corresponding to the physiological expression of rBAT can be localized by immunological methods to the microvilli of proximal straight tubules--the S3 segment of the rat tubule. This expression begins in late fetal life, and full expression occurs only after weaning. Furriols' paper reviews the pattern of experimental substrate specificity of renal cystine resorption, and is similar to that observed so far for the transporter arising in the oocytes injected with the cDNA called rBAT. For example, L-leucine and L-phenylalanine were both inhibitory, whereas L-proline and L-glutamate were not. They point out that the specific expression of rBAT protein in proximal straight tubules offers a mechanistic explanation for the compartmental heterogeneity of L-cystine resorption in the nephron.

This gradual development of rBAT expression in the developing perinatal rat is seen as perhaps related to the occurrence of "infantile cystinuria" among young people at a frequency above that expected, based on its incidence in older populations. These younger people are presumably beterozygous for cystinuria. Furriols' et al. study suggests an amplified expression of the phenotypic cystinuria alleles in cystinuric heterozygotes.(14) These authors see rBAT as a good candidate for a place as the presumed cystinuria gene and indicate that they are applying the human analog of rBAT to determine the role it plays in classical cystinuria. If that proves true, the letter "r" may be deleted from rBAT and perhaps the shortened sequence extended to the transporter itself. Might then the capital letter "B" be changed to lowercase? This would violate a questionable convention applied to gene products and would circumvent any possible confusion with an antecedent transport system of the well-recognized(6,15,16) sodium-dependent category B but would confirm a manifest place as a sodium-independent transporter.

The proposed role for rBAT as the cystinuria gene, although not necessarily as the only gene that may be involved in cystinuria, is now further confirmed by the newly communicated discovery by Palacin and his associates(17) of six mutant forms of it among cystinuric persons. rBAT mutations were characterized in 11 of 36 unrelated cystinuric subjects, among whom the most common mutation nearly abolished the transport activity characteristic of rBAT. Each of three cystinuric siblings in a Spanish family were shown homozygous for the most common mutant, both parents being heterozygous. The authors remark that this rBAT is the first gene identified to be involved in an inherited amino acid transport disorder.


1. Dent CE, Rose GA. Amino acid metabolism in cystinuria. Q J Med 1951;20:205-19

2. Vokl H, Silbernagl S. Mutual inhibition of L-cystein/L-cysteine and other neutral amino acids during tubular reabsorption, a microperfusion study in rat kidney. Pfluegers Arch 1982;395:190-5

3. Christensen HN, Cullen AM. Synthesis of metabolism-resistant substrates for the transport system for cationic amino acids, their stimulation of the release of insulin and glucagon, and of the urinary loss of amino acids related to cystinuria. Biochim Biophys Acta 1973;298:932-50

4. Christensen HN. Organic ion transport during seven decades. The amino acids. Biochim Biophys Acta 1984;779:255-69

5. Brown RR. Aminoaciduria resulting from cycloleucine administration in man. Science 1967;157:432-4

6. Christensen HN. Distinguishing amino acid transport systems of a given cell or tissue. In: Fleischer S, Fleischer B, eds. Methods of enzymology. San Diego, Calif: Academic Press, 1989:576-616

7. Bertran J, Magnanin S, Werner A, et al. Stimulation of system y(+)-like amino acid transporter by the heavy chain of human 4F2 surface antigen in Xenopus laevis oocytes. Proc Natl Acad Sci USA 1992;89:5606-10

8. Bertran J, Werner A, Chillaron J, et al. Expression cloning of a human renal cDNA that induces high affinity transport of L-cystine shared with dibasic amino acids in Xenopus oocytes. J Biol Chem 1993;268:14842-9

9. Furriols M, Chillaron J, Mora C, et al. rBAT, related to L-cystine transport, is localized to the microvilli of proximal straight tubules, and its expression is regulated in kidney by development. J Biol Chem 1993;268:27060-8

10. Van Winkle LJ, Iannacone PM, Garton RL. Transport of cationic and zwitterionic amino acids in preimplantation rat conceptuses. Dev Biol 1990;142:184-93

11. Van Winkle LJ. Endogenous amino acid transport systems and expression of mammalian amino acid transport proteins in Xenopus oocytes. Biochim Biophys Acta 1993;1154:157-72

12. Wells RG, Hediger MA. Cloning of a rat kidney cDNA that stimulates dibasic and neutral amino acid transport and has sequences similar to glucosidases. Proc Natl Acad Sci USA 1992;89:5596-600

13. Tate SS, Yan N, Udenfriend S. Expression cloning of a Na sup + -independent neutral amino acid transporter from rat kidney. Proc Natl Acad Sci USA 1992;89:1-5

14. Scriver CR, Clow CL, Terry M, et al. Ontogeny modifies manifestation of cystinuria. Implications for counseling. J Pediatr 1985;106:411-6

15. Stevens BR. Amino acid transport in intestine. In: Kilberg MS, Haussinger D, eds. Mammalian amino acid transport, mechanism, and control. New York, NY: Plenum Press, 1992:149-93

16. Doyle FA, McGivan JD. The bovine renal epithelial cell line NBL-1 expresses a broad specificity Na(+)-dependent neutral amino acid transport system (system B sup o ) similar to that in bovine renal brush-border membrane vesicles. Biochim Biophys Acta 1992;1104:55-62

17. Calonge MJ, Gasparini P, Chillaron J, et al. (M Palacin, corresponding author) Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nature Genetics 1994;6:420-25

Copyright International Life Sciences Institute and Nutrition Foundation Jun 1994
Provided by ProQuest Information and Learning Company. All rights Reserved

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