SLC22A5

Last updated
SLC22A5
Identifiers
Aliases SLC22A5 , CDSP, OCTN2, solute carrier family 22 member 5
External IDs OMIM: 603377 MGI: 1329012 HomoloGene: 68295 GeneCards: SLC22A5
Orthologs
SpeciesHumanMouse
Entrez

6584

20520

Ensembl

ENSG00000197375

ENSMUSG00000018900

UniProt

O76082

Q9Z0E8

RefSeq (mRNA)

NM_001308122
NM_003060

NM_011396
NM_001362711
NM_001362712

RefSeq (protein)

NP_001295051
NP_003051

NP_035526
NP_001349640
NP_001349641

Location (UCSC) Chr 5: 132.37 – 132.4 Mb Chr 11: 53.76 – 53.78 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] Mutations in the SLC22A5 gene cause systemic primary carnitine deficiency, which can lead to heart failure. [6]

Contents

Structure

The SLC22A5 gene, containing 10 exons, [7] is located on the q arm of chromosome 5 in position 31.1 and spans 25,910 base pair. [5] The gene produces a 63 kDa protein composed of 557 amino acids. [8] [9] 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. [10]

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. [5] 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. [11]

Clinical Significance

The main phenotypical effect of autosomal recessive mutations, either compound heterozygous or homozygous, [6] in the SLC22A5 gene is systemic primary carnitine deficiency, [7] characterized by impaired carnitine transport, urinary carnitine wasting, low serum carnitine levels, reduced intracellular carnitine accumulation, impaired beta oxidation, and cytosolic fatty acid accumulation. [6] 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. [6] [12] [13] 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. [14] The symptoms and outcome of the disease can be drastically improved by replacement therapy with L-carnitine. [15] The estimated incidence of primary carnitine deficiency in newborns is about 1 in 40,000. [16]

Interactions

SLC22A5 interacts with PDZK1. [11]

See also

Related Research Articles

<span class="mw-page-title-main">Carnitine</span> Amino acid active in mitochondria

Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into mitochondria to be oxidized for free energy production, and also participates in removing products of metabolism from cells. Given its key metabolic roles, carnitine is concentrated in tissues like skeletal and cardiac muscle that metabolize fatty acids as an energy source. Generally individuals, including strict vegetarians, synthesize enough L-carnitine in vivo.

<span class="mw-page-title-main">Dilated cardiomyopathy</span> Medical condition

Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Complications can include heart failure, heart valve disease, or an irregular heartbeat.

<span class="mw-page-title-main">Systemic primary carnitine deficiency</span> Medical condition

Systemic primary carnitine deficiency (SPCD) is an inborn error of fatty acid transport caused by a defect in the transporter responsible for moving carnitine across the plasma membrane. Carnitine is an important amino acid for fatty acid metabolism. When carnitine cannot be transported into tissues, fatty acid oxidation is impaired, leading to a variety of symptoms such as chronic muscle weakness, cardiomyopathy, hypoglycemia and liver dysfunction. The specific transporter involved with SPCD is OCTN2, coded for by the SLC22A5 gene located on chromosome 5. SPCD is inherited in an autosomal recessive manner, with mutated alleles coming from both parents.

Glutaric acidemia type 1 (GA1) is an inherited disorder in which the body is unable to completely break down the amino acids lysine, hydroxylysine and tryptophan. Excessive levels of their intermediate breakdown products can accumulate and cause damage to the brain, but particularly the basal ganglia, which are regions that help regulate movement. GA1 causes secondary carnitine deficiency, as glutaric acid, like other organic acids, is detoxified by carnitine. Mental retardation may occur.

<span class="mw-page-title-main">HADHA</span> Protein-coding gene in the species Homo sapiens

Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit is a protein that in humans is encoded by the HADHA gene. Mutations in HADHA have been associated with trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.

<span class="mw-page-title-main">Carnitine palmitoyltransferase II</span> Mammalian protein found in Homo sapiens

Carnitine O-palmitoyltransferase 2, mitochondrial is an enzyme that in humans is encoded by the CPT2 gene.

<span class="mw-page-title-main">Thiamine transporter 1</span> Mammalian protein found in Homo sapiens

Thiamine transporter 1, also known as thiamine carrier 1 (TC1) or solute carrier family 19 member 2 (SLC19A2) is a protein that in humans is encoded by the SLC19A2 gene. SLC19A2 is a thiamine transporter. Mutations in this gene cause thiamine-responsive megaloblastic anemia syndrome (TRMA), which is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anemia and sensorineural deafness.

<span class="mw-page-title-main">Folate transporter 1</span> Mammalian protein found in Homo sapiens

Folate transporter 1 is a protein which in humans is encoded by the SLC19A1 gene.

<span class="mw-page-title-main">Major facilitator superfamily</span>

The major facilitator superfamily (MFS) is a superfamily of membrane transport proteins that facilitate movement of small solutes across cell membranes in response to chemiosmotic gradients.

<span class="mw-page-title-main">SLC22A4</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 22, member 4, also known as SLC22A4, is a human gene; the encoded protein is known as the ergothioneine transporter.

<span class="mw-page-title-main">Solute carrier organic anion transporter family member 1B1</span> Protein-coding gene in the species Homo sapiens

Solute carrier organic anion transporter family member 1B1 is a protein that in humans is encoded by the SLCO1B1 gene. Pharmacogenomic research indicates that genetic variations in this gene are associated with response to simvastatin. Clinical guidelines exist that can guide dosing of simvastatin based on SLCO1B1 gene variant using genotyping or whole exome sequencing.

<span class="mw-page-title-main">SLC22A3</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 22 member 3 (SLC22A3) also known as the organic cation transporter 3 (OCT3) or extraneuronal monoamine transporter (EMT) is a protein that in humans is encoded by the SLC22A3 gene.

<span class="mw-page-title-main">SLC22A12</span> Mammalian protein found in Homo sapiens

Solute carrier family 22, member 12, also known as SLC22A12 and URAT1, is a protein which in humans is encoded by the SLC22A12 gene.

<span class="mw-page-title-main">Solute carrier organic anion transporter family member 1A2</span>

Solute carrier organic anion transporter family member 1A2 is a protein that in humans is encoded by the SLCO1A2 gene.

<span class="mw-page-title-main">Solute carrier organic anion transporter family member 2B1</span> Protein-coding gene in the species Homo sapiens

Solute carrier organic anion transporter family member 2B1 also known as organic anion-transporting polypeptide 2B1 (OATP2B1) is a protein that in humans is encoded by the gene SLCO2B1.

<span class="mw-page-title-main">Solute carrier organic anion transporter family member 4A1</span> Protein-coding gene in the species Homo sapiens

Solute carrier organic anion transporter family member 4A1 is a protein that in humans is encoded by the SLCO4A1 gene.

<span class="mw-page-title-main">Solute carrier organic anion transporter family member 3A1</span> Protein-coding gene in the species Homo sapiens

Solute carrier organic anion transporter family member 3A1 is a protein that in humans is encoded by the SLCO3A1 gene.

Solute carrier family 22, member 21 is a protein that in the house mouse is encoded by the Slc22a21 gene. The gene is also known as Octn3 and Slc22a9. Slc22a21 belongs to a protein family of solute carriers.

<span class="mw-page-title-main">Solute carrier organic anion transporter family member 2A1</span> Protein-coding gene in the species Homo sapiens

Solute carrier organic anion transporter family member 2A1, also known as the prostaglandin transporter (PGT), is a protein that in humans is encoded by the SLCO2A1 gene.

<span class="mw-page-title-main">SLC13A5</span> Protein-coding gene in humans

Solute carrier family 13 (sodium-dependent citrate transporter), member 5 also known as the Na+/citrate cotransporter or mIndy is a protein that in humans is encoded by the SLC13A5 gene. It is the mammalian homolog of the fly Indy gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000197375 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000018900 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 "Entrez Gene: SLC22A5 solute carrier family 22 (organic cation transporter), member 5" . Retrieved 2018-07-25.
  6. 1 2 3 4 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.
  7. 1 2 Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {603377}: {04/29/2015}: . World Wide Web URL: https://omim.org/
  8. ↑ 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.
  9. ↑ "SLC22A5 - Solute carrier family 22 member 5". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 2018-07-26. Retrieved 2018-07-25.
  10. ↑ 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.
  11. 1 2 "SLC22A5 - Solute carrier family 22 member 5 - Homo sapiens (Human) - SLC22A5 gene & protein". www.uniprot.org. Retrieved 2018-07-25.
  12. ↑ 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. S2CID   35640542.
  13. ↑ 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. S2CID   207687571.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.

Further reading

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