Carnitine transport: Pathophysiology and metabolism of known molecular defects

Journal of Inherited Metabolic Disease

Volumn 26, Issue 2-3, 2003, Pages 147-169

  Tein, Ingrid ^a  

^a UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID TRANSPORTER; CARNITINE; CATION TRANSPORT PROTEIN; CEPHALOSPORIN; GLUCOSE; QUINIDINE; VALPROIC ACID; VERAPAMIL;

AMINO ACID METABOLISM; AMINO ACID TRANSPORT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; AUTOSOMAL RECESSIVE DISORDER; BINDING AFFINITY; BIOCHEMISTRY; CARNITINE DEFICIENCY; CELL MEMBRANE; CHROMOSOME 11; CHROMOSOME 5Q; CONCENTRATION (PARAMETERS); DIET SUPPLEMENTATION; DRUG ABSORPTION; DRUG ELIMINATION; DRUG MEGADOSE; FIBROBLAST CULTURE; GENE LOCUS; HEART DILATATION; HETEROZYGOTE; HUMAN; HUMAN CELL; HYPERTENSION; HYPERTROPHIC CARDIOMYOPATHY; HYPOGLYCEMIC COMA; INTRACTABLE EPILEPSY; LIVER DISEASE; LYMPHOBLAST; MOLECULAR CLONING; MOLECULAR MODEL; MOUSE; MUTATIONAL ANALYSIS; NONHUMAN; PATHOPHYSIOLOGY; PHENOTYPE; POINT MUTATION; PROBABILITY; PROSPECTIVE STUDY; PROTEIN FAMILY; REVIEW; RISK ASSESSMENT; RISK FACTOR; SCREENING TEST; SIBLING; SKIN FIBROBLAST; STEATOSIS; SYNTENY;

EID: 0038042481     PISSN: 01418955     EISSN: None     Source Type: Journal    
DOI: 10.1023/A:1024481016187     Document Type: Review

References (122)

1. Appleton RE, Farrell K, Applegarth DA, Dimmick JE, Wong LT, Davidson AG (1990) The high incidence of valproate hepatotoxicity in infants may relate to familial metabolic defects. Can J Neurol Sci. 17(2): 145-148.
2. Arduini A, Mancinelli G, Radatti GL, Dottori S, Molajoni F, Ramsay RR (1992) Role of carnitine and carnitine palmitoyltransferase as integral components of the pathway for membrane phospholipid fatty acid turnover in intact human erythrocytes. J Biol Chem 267(18): 12673-12681.
3. Ater SB, Swinyard EA, Tolman KG, Madsen JA, Matsuo F (1984) Effects of SKF525A, phenobarbital, fasting, and carnitine on the anticonvulsant activity and neurotoxicity of valproate in mice. Epilepsia 25: 599-604.
4. Bahl JJ, Bressler R (1987) The pharmacology of carnitine. Annu Rev Pharmacol Toxicol 27: 257-277.
5. Bahl J, Navin T, Manian A, Bressler R (1981) Carnitine transport in isolated adult rat heart inyocytes and the effect of 7,8,-diOH chlorpromazine. Circ Res 48: 378-385.
6. Becker CM, Harris RA (1983) Influence of valproic acid on hepatic carbohydrate and lipid metabolism. Arch Biochem Biophys 223: 381-392.
7. Benavides J, Martin A, Ugarte M, Valdivieso F (1982) Inhibition by valproic acid of pyruvate uptake by brain mitochondria. Bioehem Pharmacol 31: 1633-1636.
8. Bieber LL (1988) Carnitine. Annu Rev Biochem 57: 261-283.
9. Bohan TP, Helton E, McDonald I, et al (2001) Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology 56: 1405-1409.
10. Bohles H, Richter K, Wagner-Thiessen E, Schafer H (1982) Decreased serum carnitine in valproate induced Reye syndrome. Eur J Pediatr 139:185-186.
11. Bremer J (1983) Carnitine - metabolism and functions. Physiol Rev 63: 1420-1480.
12. Burckhardt G, Wolff NA (2000) Structure of renal organic anion and cation transporters. Am J Physiol Renal Physiol 278: F853-866.
13. Burwinkel B, Kreuder J, Schweitzer S, et al (1999) Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality. Biochem Biophys Res Commun 261: 484-487.
14. Cederbaum SD, Koo-McCoy S, Tein I, et al (2002) Carnitine membrane transporter deficiency: a long-term follow up and OCTN2 mutation in the first documented case of primary carnitine deficiency. Mol Genet Metab 77: 195-201.
15. Christiansen RZ, Bremer J (1976) Active transport of butyrobetaine and carnitine into isolated liver cells. Biochim Biophys Acta 448: 562-577.
16. Corr PB, Creer MH, Yamada KA, Saffitz JE, Sobel BE (1989) Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation. J Clin Invest 83: 927-936.
17. Coulter DL (1991) Carnitine, valproate, and toxicity. J Child Neurol 6: 7-14.
18. De Vivo DC, Tein I (1990) Primary and secondary disorders of carnitine metabolism. Int Pediatr 5: 134-141.
19. Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Moline KA, Menander KB (1987) Valproic acid hepatic fatalities: a retrospective review. Neurology 37: 379-385.
20. Engel AG, Rebouche CJ, Wilson DM, Glasgow AM, Romshe CA, Cruse RP (1981) Primary systemic carnitine deficiency. II. Renal handling of carnitine. Neurology 31: 819-825.
21. Englard S (1979) Hydroxylation of γ-butyrobetaine to carnitine in human and monkey tissues. FEBS Lett 102: 297-300.
22. Eriksson BO, Gustafson B, Lindstedt S, Nordin I (1988) Hereditary defect in carnitine membrane transport is expressed in skin fibroblast. Eur J Pediatr 147: 662-663.
23. Eriksson BO, Gustafson B, Lindstedt S, Nordin I (1989) Transport of carnitine into cells in hereditary carnitine deficiency. J Inherit Metab Dis 12: 108-111.
24. Ganapathy ME, Huang W, Rajan DP, et al (2000) β-Lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter. J Biol Chem. 275(3): 1699-1707.
25. Garavaglia B, Uziel G, Dworzak F, Carrara F, DiDonato S (1991) Primary carnitine deficiency: heterozygote and intrafamilial phenotypic variation. Neurology 41: 1691-1693.
26. Gerber N, Dickinson RG, Harland RC, et al (1979) Reye-like syndrome associated with valproic acid therapy. J Pediatr 95: 142-144.
27. Haas R, Stumpf DA, Parks JK, Eguren L (1981) Inhibitory effects of sodium valproate on oxidative phosphorylation. Neurology 31: 1473-1476.
28. Hamilton JW, Li BUK, Shug A, Olsen WA (1983) Studies of L-carnitine absorption in man. Gastroeneterology 84(5 Pt 2): 1180.
29. Hannuniemi R, Kontro P (1988) L-Carnitine uptake by mouse brain synaptosomal preparations: competitive inhibition by GABA. Neurochem Res 13: 317-323.
30. Holme E, Greter J, Jacobson CE, et al (1989) Carnitine deficiency induced by pivampicillin and pivmecillinam therapy. Lancet 2(8661): 469-473.
31. Horiuchi M, Kobayashi K, Yamaguchi S, et al (1994) Primary defect of juvenile visceral steatosis (jvs) mouse with systemic carnitine deficiency is probably in renal carnitine transport system. Biochim Biophys Acta 1226: 25-30.
32. Huth PJ, Shug A (1980) Properties of carnitine transport in rat kidney cortex slices. Biochim Biophys Acta 602: 621-634.
33. Huth PJ, Thomsen JH, Shug AL (1978) Carnitine transport by rat kidney cortex slices: stimulation by dibutyryl cyclic AMP. Life Sci 23: 715-722.
34. Huth PJ, Schmidt MG, Hall PV, Fariello RG, Shug AL (1981) The uptake of carnitine by slices of rat cerebral cortex. J Neurochem 36: 715-723.
35. Kaido M, Fujimura H, Ono A, et al (1997) Mitochondrial abnormalities in a murine model of primary carnitine deficiency. Eur Neurol 38: 302-309.
36. Kay JD, Hilton-Jones D, Hyman N (1986) Valproate toxicity and ornithine carbamoyl-transferase deficiency. Lancet 2: 1283-1284.
37. Kesterson JW, Granneman GR, Machinist JM (1984) The hepatotoxicity of valproic acid and its metabolites in rats. I. Toxicologic, biochemical and histopathologic studies. Hepatology 4: 1143-1152.
38. Kispal G, Melegh B, Alkonyi I, Sandor A (1987) Enhanced uptake of carnitine by perfused rat liver following starvation. Biochim Biophys Acta 896: 96-102.
39. Koizumi A, Nozaki J-I, Ohura T (1999) Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet 8: 2247-2254.
40. Koizumi T, Nikaido H, Hayakawa J, Nonomura A, Yoneda T (1988) Infantile disease with microvesicular fatty infiltration of viscera spontaneously occurring in the C3H-H-2° strain of mouse with similarities to Reye's syndrome. Lab Anim 22: 83-87.
41. Kuwajima M, Kono N, Horiuchi M, et al (1991) Animal model of systemic carnitine deficiency: analysis in C3H-H-2° strain of mouse associated with juvenile visceral steatosis. Biochem Biophys Res Commun 174: 1090-1094.
42. Kuwajima M, Lu K-M, Harashima H, et al (1996) Carnitine transport defect in fibroblasts of juvenile visceral steatosis (JVS) mouse. Biochem Biophys Res Commun 223: 283-287.
43. Kuwajima M, Horiuchi M, Harashima H, et al (1999) Cardiomegaly in the juvenile visceral steatosis (jvs) mouse is reduced with acute elevation of heart short-chain acyl-carnitine level after L-carnitine injection. FEBS Lett 443: 261-266.
44. Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157: 105-132.
45. Lahjouji K, Elimrani I, Wu J, Mitchell GA, Qureshi IA (2002) A heterozygote phenotype is present in the jvs +/- mutant mouse livers. Mol Genet Metab 76: 76-80.
46. Lamhonwah AM, Tein I (1998) Carnitine uptake defect: frameshift mutations in the human plasmalemmal carnitine transporter gene. Biochem Biophys Res Commun 252: 396-401.
47. Lamhonwah AM, Tein I (1999) GFP-Human high-affinity carnitine transporter OCTN2 protein: subcellular localization and functional restoration of carnitine uptake in mutant cell lines with the carnitine transporter defect: Biochem Biophys Res Commun 264: 909-914.
48. Lamhonwah AM, Olpin SE, Pollitt RJ, et al (2002) Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy. Am J Med Genet 111: 271-284.
49. Laub MC, Paetzke-Brunner I, Jaeger G (1986) Serum carnitine during valproic acid therapy. Epilepsia 27: 559-562.
50. Li J, Norwood DL, Mao LF, Schulz H (1991) Mitochondrial metabolism of valproic acid. Biochemistry 30: 388-394.
51. Lu K-M, Nishimori H, Nakamura Y, et al (1998) A missense mutation of mouse OCTN2, a sodium-dependent carnitine cotransporter, in the juvenile visceral steatosis mouse. Biochem Biophys Res Commun 252: 590-594.
52. Mak IT, Kramer JH, Weglicki WB (1986) Potentiation of free radical-induced lipid peroxidative injury to sarcolemmal membranes by lipid amphiphiles. J Biol Chem 261: 1153-1157.
53. Masuda M, Kobayashi K, Horiuchi M, et al (1997) A novel gene suppressed in the ventricle of carnitine-deficient juvenile visceral steatosis mice. FEBS Lett 408: 221-224.
54. Matsuda I, Ohtani Y (1986) Carnitine status in Reye and Reye-like syndromes. Pediatr Neurol 2: 90-94.
55. Mayatepek E, Nezu J, Tamai I, et al (2000) Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency. Hum Mutat 15: 118 (Mutation in Brief (1999) 287, 1-4, Online).
56. McGarry JD, Mills SE, Long CS, Foster DW (1983) Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Biochem J 214: 21-28.
57. Melegh B, Kerner J, Kispal G, Acsadi G, Dani M (1987) Effect of chronic valproic acid treatment on plasma and urine carnitine levels in children: decreased urinary excretion. Acta Paediatr Hung 28: 137-142.
58. Millington DS, Bohan TP, Roe CR, Yergey AL, Liberato DJ (1985) Valproylcarnitine: a novel drug metabolite identified by fast atom bombardment and thermospray liquid chromatography-mass spectrometry. Clin Chim Acta 145: 69-76.
59. Molstad P, Bohmer T, Eiklid K (1977) Specificity and characteristics of the carnitine transport in human heart cells (CCL 27) in culture. Biochim Biophys Acta 471: 296-304.
60. Morita J, Yuge K, Yoshino M (1986) Hypocarnitinemia in the handicapped individuals who receive a polypharmacy of antiepileptic drugs. Neuropediatrics 17: 203-235.
61. Murphy JV, Marquardt KM, Shug A (1984) Plasma and urine carnitine concentrations in patients receiving valproic acid. Pediatr Res 18: 340 (abstract).
62. Murphy JV, Marquardt KM, Shug AL (1985) Valproic acid associated abnormalities of carnitine metabolism. Lancet 1: 820-821.
63. Nakajima T, Horiuchi M, Yamanaka H, et al (1997) The effect of carnitine on ketogenesis in perfused livers from juvenile visceral steatosis mice with systemic carnitine deficiency. Pediatr Res 42: 108-113.
64. Nezu J, Tamai I, Oku A, et al (1999) Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nature Genetics 21: 91-94.
65. Nikaido H, Horiuchi M, Hashimoto N, Saheki T, Hayakawa J (1995) Mapping of jvs (juvenile visceral steatosis) gene, which causes systemic carnitine deficiency in mice, on chromosome 11. Mamm Genome 6: 369-370.
66. Novak M, Monkus EF, Buch M, Lesmes H, Silverio J (1983) The effect of a L-carnitine supplemented soybean formula on the plasma lipids of infants. Acta Chir Scand 517 (supplement): 149-155.
67. Ohashi R, Tamai I, Yabuuchi H, et al (1999) Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J. Pharmacol Exp Ther 291: 778-784.
68. Ohashi R, Tamai I, Inano A, et al (2002) Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein. J Pharmacol Exp Ther 302: 1286-1294.
69. Olson AL, Rebouche CJ (1987) γ-Butyrobetaine hydroxylase activity is not rate limiting for carnitine biosynthesis in the human infant. J Nutr 117: 1024-1031.
70. Olson AL, Nelson SE, Rebouche CJ (1989) Low carnitine intake and altered lipid metabolism in infants. Am J Clin Nutr 49: 624-628.
71. Pons R, Carozza R, Tein I, et al (1997) Deficient muscle carnitine transport in primary carnitine deficiency. Pediatr Res 42: 583-587.
72. Pritchard JB, Miller DS (1993) Mechanisms mediating renal secretion of organic anions and cations. Physiol Rev 73: 765-796.
73. Ramsay RR, Gandour RD, van der Leij FR (2001) Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 1546: 21-43.
74. Rashed MS, Ozand PT, Bennett MJ, Barnard JJ, Govindaraju DR, Rinaldo P (1995) Inborn errors of metabolism diagnosed in sudden death cases by acylcarnitine analysis of postmortem bile. Clin Chem 41: 1109-1114.
75. Rebouche CJ (1977) Carnitine movement across muscle cell membranes. Studies in isolated rat muscle. Biochim Biophys Acta 471: 145-155.
76. Rebouche CJ (1992) Carnitine function and requirements during the life cycle. FASEB J 6: 3379-3386.
77. Rebouche CJ, Chenard CA (1991) Metabolic fate of dietary carnitine in human adults: identification and quantification of urinary and fecal metabolites. J Nutr 121: 539-546.
78. Rebouche CJ, Engel AG (1980) Tissue distribution of carnitine biosynthetic enzymes in man. Biochim Biophys Acta 630: 22-29.
79. Rebouche CJ, Engel AG (1982) Carnitine transport in cultured muscle cells and skin fibroblasts from patients with primary systemic carnitine deficiency. In Vitro 18: 495-500.
80. Rebouche CJ, Engel AG (1984) Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport. J Clin Invest 73: 857-867.
81. Rebouche CJ, Mack DL (1984) Sodium gradient-stimulated transport of L-carnitine into renal brush border membrane vesicles: kinetics, specificity, and regulation by dietary carnitine. Arch Biochem Biophys 235: 393-402.
82. Rinaldo P, Stanley CA, Hsu BY, Sanchez LA, Stern HJ (1997) Sudden neonatal death in carnitine transporter deficiency. J Pediatr 131: 304-305.
83. Rodriguez CM, Labus JC, Hinton BT (2002) Organic cation/carnitine transporter, OCTN2, is differentially expressed in the adult rat epididymis. Biol Reprod 67: 314-319.
84. Rodriguez-Segade S, de la Pena CA, Tutor JC, et al (1989) Carnitine deficiency associated with anticonvulsant therapy. Clin Chim Acta 181: 175-181.
85. Rumbach L, Warter JM, Rendon A, Marescaux C, Micheletti G, Waksman A (1983) Inhibition of oxidative phosphorylation in hepatic and cerebral mitochondria of sodium valproate-treated rats. J Neurol Sci 61: 417-423.
86. Saraste M, Sibbald PR, Wittinghofer A (1990) The P-loop - a common motif in ATP- and GTP-binding proteins. Trends Biochem Sci 15: 430-434.
87. Schulz H, Fong JC (1981) 4-Pentenoic acid. Methods Enzymol 72: 604-610.
88. Shapira Y, Gutman A (1991) Muscle carnitine deficiency in patients using valproic acid. J Pediatr 118: 646-649.
89. Shoji Y, Koizumi A, Kayo T, et al (1998) Evidence for linkage of human primary systemic carnitine deficiency with D5S436: a novel gene locus on chromosome 5q. Am J Hum Genet 63: 101-108.
90. Stanley CA (1987) New genetic defects in mitochondrial fatty acid oxidation and carnitine deficiency. Adv Pediatr 34: 59-88.
91. Stanley CA, DeLeeuw S, Coates PM, et al (1991) Chronic cardiomyopathy and weakness or acute coma in children with a defect in carmitine uptake. Ann Neurol 30: 709-716.
92. Sugimoto T, Araki A, Nishida N, et al (1987) Hepatotoxicity in rat following administration of valproic acid: effect of L-carnitine supplementation. Epilepsia 28: 373-377.
93. Tamai I, Yabuuchi H, Nezu J, et al (1997) Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett 419: 107-111.
94. Tamai I, Ohashi R, Nezu J, et al (1998) Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J Biol Chem 273: 20378-20382.
95. Tamai I, Ohashi R, Nezu JI, et al (2000) Molecular and functional characterization of organic cation /carnitine transporter family in mice. J Biol Chem 275(51): 40064-40072.
96. Tamai I, China K, Sai Y, et al (2001) Na(+)-coupled transport of L-carnitine via high-affinity carnitine transporter OCTN2 and its subcellular localization in kidney. Biochim Biophys Acta 1512: 273-284.
97. Tang NL, Ganapathy V, Wu X, et al (1999) Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency. Hum Mol Genet 8: 655-660.
98. Tein I, Xie ZW (1994) Reversal of valproic acid-associated impairment of carnitine uptake in cultured human skin fibroblasts. Biochem Biophys Res Commun 204: 753-758.
99. Tein I, Xie Z-W (1996) The human plasmalemmal carnitine transporter defect is expressed in cultured lymphoblasts: a new, rapid non-invasive diagnostic method for diagnosis. Clin Chim Acta 252: 1-4.
100. Tein I, De Vivo DC, Bierman F, et al (1990) Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy. Pediatr Res 28: 247-255.
101. Tein I, DiMauro S, Xic Z-W, De Vivo DC (1993) Valproic acid impairs carnitine uptake in cultured human skin fibroblasts. An in vitro model for the pathogenesis of valproic acid-associated carnitine deficiency. Pediatr Res 34: 281-287.
102. Tein I, DiMauro S, Xie Z-W, De Vivo DC (1995) Heterozygotes for plasmalemmal carnitine transporter defect are at increased risk for valproic acid-associated impairment of carnitine uptake in cultured human skin fibroblasts. J Inherit Metab Dis 18: 313-322.
103. Tein I, Bukovac SW, Xie Z-W (1996) Characterization of the human plasmalemmal carnitine transporter in cultured skin fibroblasts. Arch Biochem Biophys 329: 145-155.
104. Toshimori K, Kuwajima M, Yoshinaga K, et al (1999) Dysfunctions of the epididymis as a result of primary carnitine deficiency in juvenile visceral steatosis mice. FEBS Lett 446: 323-326.
105. Treem WR, Stanley CA, Finegold DN, Hale DE, Coates PM (1988) Primary carnitine deficiency due to a failure of carnitine transport in kidney, muscle and fibroblasts. N Engl J Med 319: 1331-1336.
106. Turnbull DM, Bone AJ, Bartlett K, Koundakjian PP, Sherratt HS (1983) The effects of valproate on intermediary metabolism in isolated rat hepatocytes and intact rats. Biochem Pharmacol 15(32): 1887-1892.
107. Uenaka R, Kuwajima M, Ono A, et al (1996) Increased expression of carnitine palmitoyltransferase I gene is repressed by administering L-carnitine in the hearts of carnitine-deficient juvenile visceral steatosis mice. J Biochem 119: 533-540.
108. Ullrich KJ (1994) Specificity of transporters for 'organic anions' and 'organic cations' in the kidney. Biochim Biophys Acta 1197: 45-62.
109. van Roermund CW, Hettema EH, van den Berg M, Tabak HF, Wanders RJ (1999) Molecular characterization of carnitine-dependent transport of acetyl-CoA from peroxisomes to mitochondria in Saccharomyces cerevisiae and identification of a plasma membrane carnitine transporter, Agp2p. EMBO J 18: 5843-5852.
110. Vary TC, Neely JR (1982) Characteristics of carnitine transport in isolated perfused adult rat hearts. Am J Physiol 242: H585-592.
111. Vaz FM, Scholte HR, Ruiter J, et al (1999) Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency. Hum Genet 105: 157-161.
112. Wagner CA, Lukewille U, Kaltenbach S, et al (2000) Functional and pharmacological characterization of human Na(+)-carnitine cotransporter hOCTN2. Am J Physiol Renal Physiol 279: F584-591.
113. Walker JE, Saraste M, Runswick MJ, Gay NJ (1982) Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J 1: 945-951.
114. Wang Y, Ye J, Ganapathy V, Longo N (1999) Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency. Proc Natl Acad Sci USA 96: 2356-2360.
115. Wang Y, Kelly MA, Cowan TM, Longo N (2000a) A missense mutation in the OCTN2 gene associated with residual carnitine transport activity. Hum Mutat 15: 238-245.
116. Wang Y, Taroni F, Garavaglia B, Longo N (2000b) Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency: lack of genotype-phenotype correlation. Hum Mutat 16: 401-407.
117. Willner JH, Ginsburg S, DiMauro S (1978) Active transport of carnitine into skeletal muscle. Neurology 28: 721-724.
118. Wu X, Prasad PD, Leibach FH, Ganapathy V (1998) cDNA sequence, transport function and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem Biophys Res Commun 246: 589-595.
119. Wu X, Huang W, Prasad PD, et al (1999) Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J Pharmacol Exp Ther 290: 1482-1492.
120. Wu X, George RL, Huang W, et al (2000) Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta. Biochim Biophys Acta 1466: 315-327.
121. Yabuuchi H, Tamai I, Nezu J, et al (1999) Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther 289: 768-773.
122. Zevin S, Schaner ME, Illsley NP, Giacomini KM (1997) Guanidine transport in a human choriocarcinoma cell line (JAR). Pharm Res 14: 401-405.