SLC22A5

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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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SLC22A5 is a membrane transport protein associated with primary carnitine deficiency. This protein is involved in the active cellular uptake of carnitine. It acts a symporter, moving sodium ions and other organic cations across the membrane along with carnitine. Such polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for the elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins.[1] Mutations in the SLC22A5 gene cause systemic primary carnitine deficiency, which can lead to heart failure.[2]

Structure

The SLC22A5 gene, containing 10 exons,[3] is located on the q arm of chromosome 5 in position 31.1 and spans 25,910 base pair.[1] The gene produces a 63 kDa protein composed of 557 amino acids.[4][5] The protein has 12 putative transmembrane domains, with a long extracellular loop of 107 amino acids between the first two transmembrane domains and an intracellular loop between the fourth and fifth transmembrane domains. This long extracellular loop has three potential sites for N-glycosylation, and the intracellular loop has an ATP/GTP binding motif. In putative intracellular domains, there are five potential sites for protein-kinase C-dependent phosphorylation and one for protein-kinase A-dependent phosphorylation.[6]

Function

The SLC22A5 gene codes for a plasma integral membrane protein which functions as both an organic cation transporter and a sodium-dependent high affinity carnitine transporter.[1] The encoded protein is involved in the active cellular uptake of carnitine, transporting one sodium ion with one molecule of carnitine. Organic cations transported by this protein include tetraethylammonium (TEA) without involvement of sodium. The relative uptake activity ratio of carnitine to TEA is 11.3.[7]

Clinical Significance

The main phenotypical effect of autosomal recessive mutations, either compound heterozygous or homozygous,[2] in the SLC22A5 gene is systemic primary carnitine deficiency,[3] characterized by impaired carnitine transport, urinary carnitine wasting, low serum carnitine levels, reduced intracellular carnitine accumulation, impaired beta oxidation, and cytosolic fatty acid accumulation.[2] Patients often display metabolic decompensation, hypoketotic hypoglycemia, hepatic encephalopathy, Reye syndrome, and sudden infant death in their first year, followed by the later onset of cardiomyopathy or skeletal myopathy, arrhythmias, muscle weakness, and heart failure in early childhood.[2][8][9] Patients may be asymptomatic, with about 70% of asymptomatic patients having a missense mutation or in-frame deletion; nonsense mutation frequency is increased in symptomatic patients.[10] The symptoms and outcome of the disease can be drastically improved by replacement therapy with L-carnitine.[11] The estimated incidence of primary carnitine deficiency in newborns is about 1 in 40,000.[12]

Interactions

SLC22A5 interacts with PDZK1.[7]

See also

References

  1. ↑ 1.0 1.1 1.2 "Entrez Gene: SLC22A5 solute carrier family 22 (organic cation transporter), member 5". Retrieved 2018-07-25.
  2. ↑ 2.0 2.1 2.2 2.3 Lahrouchi N, Lodder EM, Mansouri M, Tadros R, Zniber L, Adadi N, Clur SB, van Spaendonck-Zwarts KY, Postma AV, Sefiani A, Ratbi I, Bezzina CR (June 2017). "Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death". European Journal of Human Genetics. 25 (6): 783–787. doi:10.1038/ejhg.2017.22. PMC 5477358. PMID 28295041.
  3. ↑ 3.0 3.1 Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {603377}: {04/29/2015}: . World Wide Web URL: https://omim.org/
  4. ↑ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  5. ↑ "SLC22A5 - Solute carrier family 22 member 5". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  6. ↑ Wu X, Prasad PD, Leibach FH, Ganapathy V (May 1998). "cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family". Biochemical and Biophysical Research Communications. 246 (3): 589–95. doi:10.1006/bbrc.1998.8669. PMID 9618255.
  7. ↑ 7.0 7.1 "SLC22A5 - Solute carrier family 22 member 5 - Homo sapiens (Human) - SLC22A5 gene & protein". www.uniprot.org. Retrieved 2018-07-25.
  8. ↑ Yilmaz TF, Atay M, Toprak H, Guler S, Aralasmak A, Alkan A (2014-03-10). "MRI findings in encephalopathy with primary carnitine deficiency: a case report". Journal of Neuroimaging. 25 (2): 325–328. doi:10.1111/jon.12102. PMID 24612242.
  9. ↑ Mazzini M, Tadros T, Siwik D, Joseph L, Bristow M, Qin F, Cohen R, Monahan K, Klein M, Colucci W (2011). "Primary carnitine deficiency and sudden death: in vivo evidence of myocardial lipid peroxidation and sulfonylation of sarcoendoplasmic reticulum calcium ATPase 2". Cardiology. 120 (1): 52–8. doi:10.1159/000333127. PMID 22116472.
  10. ↑ Yoon YA, Lee DH, Ki CS, Lee SY, Kim JW, Lee YW, Park HD (2012). "SLC22A5 mutations in a patient with systemic primary carnitine deficiency: the first Korean case confirmed by biochemical and molecular investigation". Annals of Clinical and Laboratory Science. 42 (4): 424–8. PMID 23090741.
  11. ↑ Agnetti A, Bitton L, Tchana B, Raymond A, Carano N (January 2013). "Primary carnitine deficiency dilated cardiomyopathy: 28 years follow-up". International Journal of Cardiology. 162 (2): e34–5. doi:10.1016/j.ijcard.2012.05.038. PMID 22658351.
  12. ↑ Koizumi A, Nozaki J, Ohura T, Kayo T, Wada Y, Nezu J, Ohashi R, Tamai I, Shoji Y, Takada G, Kibira S, Matsuishi T, Tsuji A (November 1999). "Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency". Human Molecular Genetics. 8 (12): 2247–54. PMID 10545605.

Further reading

  • Ascunce RR, Nayar AC, Phoon CK, Srichai MB (2013). "Cardiac magnetic resonance findings in a case of carnitine deficiency". Texas Heart Institute Journal. 40 (1): 104–5. PMID 23468586.
  • Erguven M, Yilmaz O, Koc S, Caki S, Ayhan Y, Donmez M, Dolunay G (2007). "A case of early diagnosed carnitine deficiency presenting with respiratory symptoms". Annals of Nutrition & Metabolism. 51 (4): 331–4. doi:10.1159/000107675. PMID 17726310.
  • Hwu WL, Chien YH, Tang NL, Law LK, Lin CY, Lee NC (October 2007). "Deficiency of the carnitine transporter (OCTN2) with partial N-acetylglutamate synthase (NAGS) deficiency". Journal of Inherited Metabolic Disease. 30 (5): 816. doi:10.1007/s10545-007-0594-y. PMID 17703373.
  • Makhseed N, Vallance HD, Potter M, Waters PJ, Wong LT, Lillquist Y, Pasquali M, Amat di San Filippo C, Longo N (2004). "Carnitine transporter defect due to a novel mutation in the SLC22A5 gene presenting with peripheral neuropathy". Journal of Inherited Metabolic Disease. 27 (6): 778–80. PMID 15617188.
  • Kinali M, Olpin SE, Clayton PT, Daubeney PE, Mercuri E, Manzur AY, Tein I, Leonard J, Muntoni F (2004). "Diagnostic difficulties in a case of primary systemic carnitine deficiency with idiopathic dilated cardiomyopathy". European Journal of Paediatric Neurology. 8 (4): 217–9. doi:10.1016/j.ejpn.2004.03.007. PMID 15261886.
  • Kinali M, Olpin SE, Clayton PT, Daubeney PE, Mercuri E, Manzur AY, Tein I, Leonard J, Muntoni F (2004). "Diagnostic difficulties in a case of primary systemic carnitine deficiency with idiopathic dilated cardiomyopathy". European Journal of Paediatric Neurology. 8 (4): 217–9. doi:10.1016/j.ejpn.2004.03.007. PMID 15261886.
  • Silverberg MS (June 2006). "OCTNs: will the real IBD5 gene please stand up?". World Journal of Gastroenterology. 12 (23): 3678–81. doi:10.3748/wjg.v12.i23.3678. PMC 4087460. PMID 16773684.
  • Matsuishi T, Hirata K, Terasawa K, Kato H, Yoshino M, Ohtaki E, Hirose F, Nonaka I, Sugiyama N, Ohta K (February 1985). "Successful carnitine treatment in two siblings having lipid storage myopathy with hypertrophic cardiomyopathy". Neuropediatrics. 16 (1): 6–12. doi:10.1055/s-2008-1052536. PMID 3974805.
  • Wu X, Prasad PD, Leibach FH, Ganapathy V (May 1998). "cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family". Biochemical and Biophysical Research Communications. 246 (3): 589–95. doi:10.1006/bbrc.1998.8669. PMID 9618255.
  • Shoji Y, Koizumi A, Kayo T, Ohata T, Takahashi T, Harada K, Takada G (July 1998). "Evidence for linkage of human primary systemic carnitine deficiency with D5S436: a novel gene locus on chromosome 5q". American Journal of Human Genetics. 63 (1): 101–8. doi:10.1086/301911. PMC 1377235. PMID 9634512.
  • Tamai I, Ohashi R, Nezu J, Yabuuchi H, Oku A, Shimane M, Sai Y, Tsuji A (August 1998). "Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2". The Journal of Biological Chemistry. 273 (32): 20378–82. doi:10.1074/jbc.273.32.20378. PMID 9685390.
  • Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N, Nikaido H, Sai Y, Koizumi A, Shoji Y, Takada G, Matsuishi T, Yoshino M, Kato H, Ohura T, Tsujimoto G, Hayakawa J, Shimane M, Tsuji A (January 1999). "Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter". Nature Genetics. 21 (1): 91–4. doi:10.1038/5030. PMID 9916797.
  • Tang NL, Ganapathy V, Wu X, Hui J, Seth P, Yuen PM, Wanders RJ, Fok TF, Hjelm NM (April 1999). "Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency". Human Molecular Genetics. 8 (4): 655–60. doi:10.1093/hmg/8.4.655. PMID 10072434.
  • Burwinkel B, Kreuder J, Schweitzer S, Vorgerd M, Gempel K, Gerbitz KD, Kilimann MW (August 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". Biochemical and Biophysical Research Communications. 261 (2): 484–7. doi:10.1006/bbrc.1999.1060. PMID 10425211.
  • Wu X, Huang W, Prasad PD, Seth P, Rajan DP, Leibach FH, Chen J, Conway SJ, Ganapathy V (September 1999). "Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter". The Journal of Pharmacology and Experimental Therapeutics. 290 (3): 1482–92. PMID 10454528.
  • Vaz FM, Scholte HR, Ruiter J, Hussaarts-Odijk LM, Pereira RR, Schweitzer S, de Klerk JB, Waterham HR, Wanders RJ (1999). "Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency". Human Genetics. 105 (1–2): 157–61. doi:10.1007/s004390051079. PMID 10480371.
  • Koizumi A, Nozaki J, Ohura T, Kayo T, Wada Y, Nezu J, Ohashi R, Tamai I, Shoji Y, Takada G, Kibira S, Matsuishi T, Tsuji A (November 1999). "Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency". Human Molecular Genetics. 8 (12): 2247–54. doi:10.1093/hmg/8.12.2247. PMID 10545605.
  • Seth P, Wu X, Huang W, Leibach FH, Ganapathy V (November 1999). "Mutations in novel organic cation transporter (OCTN2), an organic cation/carnitine transporter, with differential effects on the organic cation transport function and the carnitine transport function". The Journal of Biological Chemistry. 274 (47): 33388–92. doi:10.1074/jbc.274.47.33388. PMID 10559218.
  • Mayatepek E, Nezu J, Tamai I, Oku A, Katsura M, Shimane M, Tsuji A (January 2000). "Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency". Human Mutation. 15 (1): 118. doi:10.1002/(SICI)1098-1004(200001)15:1<118::AID-HUMU28>3.0.CO;2-8. PMID 10612840.
  • Wang Y, Kelly MA, Cowan TM, Longo N (2000). "A missense mutation in the OCTN2 gene associated with residual carnitine transport activity". Human Mutation. 15 (3): 238–45. doi:10.1002/(SICI)1098-1004(200003)15:3<238::AID-HUMU4>3.0.CO;2-3. PMID 10679939.
  • Ohashi R, Tamai I, Inano A, Katsura M, Sai Y, Nezu J, Tsuji A (September 2002). "Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein". The Journal of Pharmacology and Experimental Therapeutics. 302 (3): 1286–94. doi:10.1124/jpet.102.036004. PMID 12183691.
  • Rahbeeni Z, Vaz FM, Al-Hussein K, Bucknall MP, Ruiter J, Wanders RJ, Rashed MS (September 2002). "Identification of two novel mutations in OCTN2 from two Saudi patients with systemic carnitine deficiency". Journal of Inherited Metabolic Disease. 25 (5): 363–9. doi:10.1023/A:1020143632011. PMID 12408185.
  • Elimrani I, Lahjouji K, Seidman E, Roy MJ, Mitchell GA, Qureshi I (May 2003). "Expression and localization of organic cation/carnitine transporter OCTN2 in Caco-2 cells". American Journal of Physiology. Gastrointestinal and Liver Physiology. 284 (5): G863–71. doi:10.1152/ajpgi.00220.2002. PMID 12684216.
  • Karlic H, Lohninger A, Laschan C, Lapin A, Böhmer F, Huemer M, Guthann E, Rappold E, Pfeilstöcker M (July 2003). "Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes". Journal of Molecular Medicine. 81 (7): 435–42. doi:10.1007/s00109-003-0447-6. PMID 12802501.
  • Amat di San Filippo C, Wang Y, Longo N (November 2003). "Functional domains in the carnitine transporter OCTN2, defective in primary carnitine deficiency". The Journal of Biological Chemistry. 278 (48): 47776–84. doi:10.1074/jbc.M307911200. PMID 14506273.

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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