Lysinuric protein intolerance, an autosomal recessive disease

Lysinuric protein intolerance (LPI) is characterized by failure to thrive, diarrhea and vomiting associated with protein intake, aversion to protein-rich food, growth retardation, hepatomegaly, hyperammonemia, and deficient urea formation after an amino nitrogen load, and increased urinary excretion of basic amino acids, especially lysine. LPI has been diagnosed in 16 patients of 10 families in Finland and in one Finnish immigrant in Sweden. In this study data were evaluated to test the autosomal recessive transmission of LPI.
In 6 families out of 10 the occurrence was familial. The sex ratio of those affected was 6 : 10. The proportion of affected sibs, corrected by Apert's a priori method, was 0.26. In 5 families the parental marriage was consanguineous, and in two groups of two families all four parents were descendants of one ancestor pair. The geographical distribution of the LPI ancestors was uneven as is true for many rare recessive diseases in Finland. No heterozygous effects of the LPI gene could be detected with certainty. These finclings constitute evidence in favor of the autosomal recessive transmission of LPI.     

Lysinuric protein intolerance: reviewing concepts on a multisystem disease

Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid transport at the basolateral membrane of epithelial cells in intestine and kidney. LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. LPI was initially described in Finland, but has worldwide distribution. Typically, symptoms begin after weaning with refusal of feeding, vomiting, and consequent failure to thrive. Hepatosplenomegaly, hematological anomalies, neurological involvement, including hyperammonemic coma are recurrent clinical features. Two major complications, pulmonary alveolar proteinosis and renal disease are increasingly observed in LPI patients. There is extreme variability in the clinical presentation even within individual families, frequently leading to misdiagnosis or delayed diagnosis. This condition is diagnosed by urine amino acids, showing markedly elevated excretion of lysine and other dibasic amino acids despite low plasma levels of lysine, ornithine, and arginine. The biochemical diagnosis can be uncertain, requiring confirmation by DNA testing. So far, approximately 50 different mutations have been identified in the SLC7A7 gene in a group of 142 patients from 110 independent families. No genotype-phenotype correlation could be established. Therapy requires a low protein diet, low-dose citrulline supplementation, nitrogen-scavenging compounds to prevent hyperammonemia, lysine, and carnitine supplements. Supportive therapy is available for most complications with bronchoalveolar lavage being necessary for alveolar proteinosis.     

Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene

Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in the intestine and kidney. LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. Coexpression of 4F2hc (the heavy chain subunit) and y(+)LAT-1 induces y(+)L activity (CAA transport). So far a total of 43 different mutations of the SLC7A7 gene, nine of which newly reported here, have been identified in a group of 130 patients belonging to at least 98 independent families. The mutations are distributed along the entire gene and include all different types of mutations. Five polymorphisms within the SLC7A7 coding region and two variants found in the 5'UTR have been identified. A genuine founder effect mutation has been demonstrated only in Finland, where LPI patients share the same homozygous mutation, c.895-2A>T. LPI patients show extreme variability in clinical presentation, and no genotype-phenotype correlations have been defined. This phenotypic variability and the lack of a specific clinical presentation have caused various misdiagnoses. At the biochemical level, the elucidation of SLC7A7 function will be necessary to understand precise disease mechanisms and develop more specific and effective therapies. In this review, we summarize the current knowledge of SLC7A7 mutations and their role in LPI pathogenesis.     

Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder

Lysinuric protein intolerance (LPI) is an inherited defect of cationic amino acid (lysine, arginine and ornithine) transport at the basolateral membrane of intestinal and renal tubular cells caused by mutations in SLC7A7 encoding the y(+)LAT1 protein. LPI has long been considered a relatively benign urea cycle disease, when appropriately treated with low-protein diet and l-citrulline supplementation. However, the severe clinical course of this disorder suggests that LPI should be regarded as a severe multisystem disease with uncertain outcome. Specifically, immune dysfunction potentially attributable to nitric oxide (NO) overproduction secondary to arginine intracellular trapping (due to defective efflux from the cell) might be a crucial pathophysiological route explaining many of LPI complications. The latter comprise severe lung disease with pulmonary alveolar proteinosis, renal disease, hemophagocytic lymphohistiocytosis with subsequent activation of macrophages, various auto-immune disorders and an incompletely characterized immune deficiency. These results have several therapeutic implications, among which lowering the l-citrulline dosage may be crucial, as excessive citrulline may worsen intracellular arginine accumulation.     

Hypocarnitinemia in lysinuric protein intolerance

Carnitine deficiency in lysinuric protein intolerance (LPI) has been reported only in a single case. We describe hypocarnitinemia in a 11 year-old male patient with LPI and relate its development to intake, biosynthesis, and uptake of carnitine.     

Necropsy findings in lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is a rare autosomal recessive inborn error of metabolism, characterised by defective transport of the cationic amino acids lysine, arginine and ornithine. To date there are few reported necropsy cases. This report describes the necropsy findings in a 21 year old female patient originally diagnosed as having LPI in 1973. Liver function tests deteriorated and immediately before death jaundice, hyperammonaemia, coma, metabolic acidosis, and a severe bleeding diathesis developed. At necropsy, there was micronodular cirrhosis of the liver with extensive fatty change in hepatocytes. The lungs showed pulmonary alveolar proteinosis. Immunofluorescence and electron microscopy revealed the presence of a glomerulonephritis with predominant IgA deposition. These necropsy findings reflect the spectrum of lesions reported in LPI, providing further evidence of an association between this condition and pulmonary alveolar proteinosis, cirrhosis and glomerulonephritis.     

Value of lymphoblast transformation test in cow's milk protein intestinal intolerance

Lymphoblast transformation tests were carried out in the presence of α-lactalbumin and β-lactoglobulin. In patients with cow's milk protein intestinal intolerance in seventeen of forty-five (37·8%) the lymphoblast transformation tests were positive. Sensitization in the first month of life seemed to favour lymphoblast transformation. In control children in only four of forty-three (9·5%) the lymphoblast transformation tests were positive, the difference from intolerant patients being significant 0·01 < P < 0·001. Lymphoblast transformation tests were negative in the seven children with active coeliac disease. Although a negative test does not exclude cow's milk protein intolerance, lymphoblast transformation tests can be considered a useful aid in diagnosis because of its specificity.     

Redox-dependent protein kinase regulation by angiotensin II: mechanistic insights and its pathophysiology

Reactive oxygen species (ROS) are proposed to induce cardiovascular diseases, such as atherosclerosis, hypertension, restenosis, and fibrosis, through several mechanisms. One such mechanism involves ROS acting as intracellular second messengers, which lead to induction of unique signal transductions. Angiotensin II (AngII), a potent cardiovascular pathogen, stimulates ROS production through the G protein-coupled AngII type 1 receptor expressed in its target organs, such as vascular tissues, heart, and kidney. Recent accumulating evidence indicates that through ROS production, AngII activates downstream ROS-sensitive kinases that are critical in mediating cardiovascular remodeling. Each of these ROS-sensitive kinases could potentially mediate its own specific function. In this review, we will focus our discussion on the current findings that suggest novel mechanisms of how AngII mediates activation of these redox-sensitive kinases in target organs, as well as the pathological significance of their activation.     

The first korean case of lysinuric protein intolerance: presented with short stature and increased somnolence

Lysinuric protein intolerance (LPI) is a rare inherited metabolic disease, caused by defective transport of dibasic amino acids. Failure to thrive, hepatosplenomegaly, hematological abnormalities, and hyperammonemic crisis are major clinical features. However, there has been no reported Korean patient with LPI as of yet. We recently encountered a 3.7-yr-old Korean girl with LPI and the diagnosis was confirmed by amino acid analyses and the SLC7A7 gene analysis. Her initial chief complaint was short stature below the 3rd percentile and increased somnolence for several months. Hepatosplenomegaly was noted, as were anemia, leukopenia, elevated levels of ferritin and lactate dehydrogenase, and hyperammonemia. Lysine, arginine, and ornithine levels were low in plasma and high in urine. The patient was a homozygote with a splicing site mutation of IVS4+1G > A in the SLC7A7. With the implementation of a low protein diet, sodium benzoate, citrulline and L-carnitine supplementation, anemia, hyperferritinemia, and hyperammonemia were improved, and normal growth velocity was observed.     

Specific antibodies in infants with gastrointestinal intolerance to cow's milk protein

Antibodies of various immunoglobulin classes against cow's milk proteins were studied in infants and children with cow's milk protein intolerance, gluten-sensitive enteropathy and acute gastroenteritis. Their IgE, IgG, IgM and IgA antibody levels determined with the enzyme-linked immunosorbent assay (ELISA) and the IgE antibodies also determined with RAST, were compared with reference groups of children and adults. IgE, IgT or IgA antibodies against unseparated cow's milk proteins, alpha-lactalbumin, beta-lactoglobulin, alpha-casein and beta-casein were present in many of the studied samples, but did not discriminate between the individuals with and without intolerance symptoms. As a group, the infants with late reactions to cow's milk showed increased levels of IgE and IgG antibodies detected with the ELISA, while patients with gluten-sensitive enteropathy had significantly increased levels of IgG and IgA antibodies of cow's milk proteins compared to the reference group. By combining the findings of antibody increases in various immunoglobulin classes, an individual discrimination could be reached. Thus, 8 of 9 of the patients with late reactions to cow's milk had increased levels of IgE or IgG + IgA antibodies as compared to 3 of 22 in the reference group. Serodiagnosis with the ELISA may, therefore, be of some use in patients with a suspicion of cow's milk protein intolerance.     

Impaired phagocytosis in macrophages from patients affected by lysinuric protein intolerance

Lysinuric Protein Intolerance (LPI, MIM 222700) is a recessive aminoaciduria caused by defective cationic amino acid transport in epithelial cells of intestine and kidney. SLC7A7, the gene mutated in LPI, codifies for the y+LAT1 subunit of system y(+)L amino acid transporter. LPI patients frequently display severe complications, such as pulmonary disease, haematological abnormalities and disorders of the immune response. The transport defect may explain only a part of the clinical aspects of the disease, while the mechanisms linking the genetic defect to the clinical features of the patients remain thus far obscure. The aim of the study is to investigate the consequences of SLC7A7 mutations on specific macrophage functions, so as to evaluate if a macrophage dysfunction may have a role in the development of pulmonary and immunological complications of LPI. The results presented 1) confirm previous data obtained in one LPI patient, demonstrating that arginine influx through system y(+)L is markedly compromised in LPI macrophages; 2) demonstrate that also system y(+)L-mediated arginine efflux is significantly lower in LPI macrophages than in normal cells and 3) demonstrate that the phagocytic activity of LPI macrophages is severely impaired. In conclusion, SLC7A7/y+LAT1 mutations lead to a defective phenotype of macrophages, supporting the pathogenetic role of these cells in the development of LPI-associated complications.     

Anchoring of aquaporin-4 in brain: molecular mechanisms and implications for the physiology and pathophysiology of water transport

Astrocytes show an enrichment of aquaporin-4 (AQP4) in those parts of the plasma membrane that are apposed to pial or perivascular basal laminae. This observation begged the following questions: 1, What are the molecular mechanisms that are responsible for the site specific anchoring of AQP4? 2, What are the physiological and pathophysiological roles of the AQP4 pools at these specialized membrane domains? Recent studies suggest that the site specific anchoring depends on the dystrophin complex. Further, alpha-syntrophin (a member of the dystrophin complex) is required to maintain a polarized expression of AQP4 in the perivascular membranes. Hence transgenic mice deficient in alpha-syntrophin provided a model where the perivascular pool of AQP4 could be removed for assessment of its functional roles. Data suggest that the perivascular pool of AQP4 plays a role in edema formation and that this pool (through its serial coupling with the AQP4 pools in other astrocyte membranes) is involved in K(+) siphoning. In the cerebral cortex, the astrocyte membrane domain contacting the pial basal lamina differs from the perivascular membrane domain in regard to the mechanisms for AQP anchoring. Thus deletion of alpha-syntrophin causes only a 50% loss of AQP4 from the former membrane (compared with a 90% loss in the latter), pointing to the existence of additional anchoring proteins. We will also discuss the subcellular distribution and anchoring of AQP4 in the other cell types that express this protein: endothelial cells, ependymal cells, and the specialized astrocytes of the osmosensitive organs.     

Role of the cAMP-binding protein Epac in cardiovascular physiology and pathophysiology

Exchange proteins directly activated by cyclic AMP (Epac) were discovered 10 years ago as new sensors for the second messenger cyclic AMP (cAMP). Epac family, including Epac1 and Epac2, are guanine nucleotide exchange factors for the Ras-like small GTPases Rap1 and Rap2 and function independently of protein kinase A. Given the importance of cAMP in the cardiovascular system, numerous molecular and cellular studies using specific Epac agonists have analyzed the role and the regulation of Epac proteins in cardiovascular physiology and pathophysiology. The specific functions of Epac proteins may depend upon their microcellular environments as well as their expression and localization. This review discusses recent data showing the involvement of Epac in vascular cell migration, endothelial permeability, and inflammation through specific signaling pathways. In addition, we present evidence that Epac regulates the activity of various cellular compartments of the cardiac myocyte and influences calcium handling and excitation–contraction coupling. The potential role of Epac in cardiovascular disorders such as cardiac hypertrophy and remodeling is also discussed.     

Titin as a modular spring: emerging mechanisms for elasticity control by titin in cardiac physiology and pathophysiology

Titin is a giant elastic protein that functions as a molecular spring that develops passive muscle stiffness. Here we discuss the molecular basis of titin's extensibility, how titin's contribution to passive muscle stiffness may be adjusted and how adjustment of titin's stiffness may influence muscle contraction. We also focus on ligands that link titin to membrane channel activity, protein turnover and gene expression.