SLC22A5: Difference between revisions

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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
{{Infobox_gene}}
'''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 [[Ion#Anions_and_cations |cations]] across the membrane along with carnitine. Such polyspecific [[Organic cation transport proteins |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.<ref name="entrez" /> Mutations in the ''SLC22A5'' gene cause [[systemic primary carnitine deficiency]], which can lead to [[heart failure]].<ref name=":2" />
'''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 [[Ion#Anions and cations|cations]] across the membrane along with carnitine. Such polyspecific [[Organic cation transport proteins|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.<ref name="entrez" /> Mutations in the ''SLC22A5'' gene cause [[systemic primary carnitine deficiency]], which can lead to [[heart failure]].<ref name=":2" />
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== Structure ==
== Structure ==
The ''SLC22A5'' gene, containing 10 exons,<ref name=":0">Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {603377}: {04/29/2015}: . World Wide Web URL: https://omim.org/</ref> is located on the q arm of [[chromosome 5]] in position 31.1 and spans 25,910 base pair.<ref name = "entrez"/> The gene produces a 63 kDa protein composed of 557 [[amino acids]].<ref name="COPaKB">{{cite journal | vauthors = 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 | title = Integration of cardiac proteome /biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = Oct 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref><ref name="url_COPaKB">{{cite web | url = https://amino.heartproteome.org/web/protein/O76082 | work = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = SLC22A5 - Solute carrier family 22 member 5 }}</ref> 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-linked glycosylation |N-glycosylation]], and the intracellular loop has an [[ATP-binding motif |ATP/GTP binding motif]]. In putative intracellular domains, there are five potential sites for [[Protein kinase C |protein-kinase C-dependent]] phosphorylation and one for [[Protein kinase A |protein-kinase A-dependent phosphorylation]].<ref>{{Cite journal|last=Wu|first=Xiang|last2=Prasad|first2=Puttur D.|last3=Leibach|first3=Frederick H.|last4=Ganapathy|first4=Vadivel|date=1998-05|title=cDNA Sequence, Transport Function, and Genomic Organization of Human OCTN2, a New Member of the Organic Cation Transporter Family|url=http://linkinghub.elsevier.com/retrieve/pii/S0006291X98986697|journal=Biochemical and Biophysical Research Communications|volume=246|issue=3|pages=589–595|doi=10.1006/bbrc.1998.8669|issn=0006-291X}}</ref>
The ''SLC22A5'' gene, containing 10 exons,<ref name=":0">Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {603377}: {04/29/2015}: . World Wide Web URL: https://omim.org/</ref> is located on the q arm of [[chromosome 5]] in position 31.1 and spans 25,910 base pair.<ref name = "entrez"/> The gene produces a 63 kDa protein composed of 557 [[amino acids]].<ref name="COPaKB">{{cite journal | vauthors = 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 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref><ref name="url_COPaKB">{{cite web | url = https://amino.heartproteome.org/web/protein/O76082 | work = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = SLC22A5 - Solute carrier family 22 member 5 | access-date = 2018-07-25 | archive-date = 2018-07-26 | archive-url = https://web.archive.org/web/20180726040930/https://amino.heartproteome.org/web/protein/O76082 | url-status = dead }}</ref> 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-linked glycosylation|N-glycosylation]], and the intracellular loop has an [[ATP-binding motif|ATP/GTP binding motif]]. In putative intracellular domains, there are five potential sites for [[Protein kinase C|protein-kinase C-dependent]] phosphorylation and one for [[Protein kinase A|protein-kinase A-dependent phosphorylation]].<ref>{{cite journal | vauthors = Wu X, Prasad PD, Leibach FH, Ganapathy V | title = cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family | journal = Biochemical and Biophysical Research Communications | volume = 246 | issue = 3 | pages = 589–95 | date = May 1998 | pmid = 9618255 | doi = 10.1006/bbrc.1998.8669 }}</ref>


== Function ==
== Function ==
The ''SLC22A5'' gene codes for a plasma [[integral membrane protein]] which functions as both an [[Organic cation transport proteins |organic cation transporter]] and a sodium-dependent high affinity [[carnitine]] transporter.<ref name="entrez">{{cite web | title = Entrez Gene: SLC22A5 solute carrier family 22 (organic cation transporter), member 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6584| accessdate =2018-07-25}}</ref> The encoded protein is involved in the active cellular uptake of carnitine, transporting one [[Sodium_in_biology |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.<ref name=":1">{{Cite web|url=https://www.uniprot.org/uniprot/O76082|title=SLC22A5 - Solute carrier family 22 member 5 - Homo sapiens (Human) - SLC22A5 gene & protein|website=www.uniprot.org|language=en|access-date=2018-07-25}}</ref>
The ''SLC22A5'' gene codes for a plasma [[integral membrane protein]] which functions as both an [[Organic cation transport proteins|organic cation transporter]] and a sodium-dependent high affinity [[carnitine]] transporter.<ref name="entrez">{{cite web | title = Entrez Gene: SLC22A5 solute carrier family 22 (organic cation transporter), member 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6584| access-date =2018-07-25}}</ref> The encoded protein is involved in the active cellular uptake of carnitine, transporting one [[Sodium in biology|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.<ref name=":1">{{Cite web|url=https://www.uniprot.org/uniprot/O76082|title=SLC22A5 - Solute carrier family 22 member 5 - Homo sapiens (Human) - SLC22A5 gene & protein|website=www.uniprot.org|language=en|access-date=2018-07-25}}</ref>


== Clinical Significance ==
== Clinical Significance ==
The main [[Phenotype |phenotypical]] effect of autosomal recessive mutations, either [[Compound heterozygosity|compound heterozygous]] or [[Zygosity#Homozygous |homozygous]],<ref name=":2">{{cite journal |last1=Lahrouchi |first1=Najim |last2=Lodder |first2=Elisabeth M |last3=Mansouri |first3=Maria |last4=Tadros |first4=Rafik |last5=Zniber |first5=Layla |last6=Adadi |first6=Najlae |last7=Clur |first7=Sally-Ann B |last8=van Spaendonck-Zwarts |first8=Karin Y |last9=Postma |first9=Alex V |last10=Sefiani |first10=Abdelaziz |last11=Ratbi |first11=Ilham |last12=Bezzina |first12=Connie R |title=Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death |journal=European Journal of Human Genetics |date=15 March 2017 |volume=25 |issue=6 |pages=783–787 |doi=10.1038/ejhg.2017.22 |pmid=28295041 |accessdate=2018-07-25}}</ref> in the ''SLC22A5'' gene is [[systemic primary carnitine deficiency]],<ref name=":0" /> characterized by impaired carnitine transport, urinary carnitine wasting, low serum carnitine levels, reduced intracellular carnitine accumulation, impaired [[beta oxidation]], and [[cytosol |cytosolic]] [[fatty acid]] accumulation.<ref name=":2" /> Patients often display metabolic decompensation, [[Carnitine-acylcarnitine_translocase_deficiency#Presentation |hypoketotic hypoglycemia]], [[hepatic encephalopathy]], [[Reye syndrome]], and [[Sudden infant death syndrome |sudden infant death]] in their first year, followed by the later onset of [[cardiomyopathy]] or [[Skeletal muscle |skeletal]] [[myopathy]], [[Heart arrhythmia |arrhythmias]], muscle weakness, and heart failure in early childhood.<ref name=":2" /><ref>{{Cite journal|last=Yilmaz|first=Temel Fatih|last2=Atay|first2=Musa|last3=Toprak|first3=Huseyin|last4=Guler|first4=Serhat|last5=Aralasmak|first5=Ayse|last6=Alkan|first6=Alpay|date=2014-03-10|title=MRI Findings in Encephalopathy with Primary Carnitine Deficiency: A Case Report|url=http://doi.wiley.com/10.1111/jon.12102|journal=Journal of Neuroimaging|language=en|volume=25|issue=2|pages=325–328|doi=10.1111/jon.12102|issn=1051-2284}}</ref><ref name=":3">{{Cite journal|last=Mazzini|first=M.|last2=Tadros|first2=T.|last3=Siwik|first3=D.|last4=Joseph|first4=L.|last5=Bristow|first5=M.|last6=Qin|first6=F.|last7=Cohen|first7=R.|last8=Monahan|first8=K.|last9=Klein|first9=M.|date=2011|title=Primary Carnitine Deficiency and Sudden Death: In vivo Evidence of Myocardial Lipid Peroxidation and Sulfonylation of Sarcoendoplasmic Reticulum Calcium ATPase 2|url=https://www.karger.com/Article/FullText/333127|journal=Cardiology|language=english|volume=120|issue=1|pages=52–58|doi=10.1159/000333127|issn=0008-6312}}</ref> Patients may be [[asymptomatic]], with about 70% of asymptomatic patients having a [[missense mutation]] or [[Deletion_(genetics)#Effects |in-frame deletion]]; [[nonsense mutation]] frequency is increased in symptomatic patients.<ref>{{Cite journal|last=Yoon|first=Young Ahn|last2=Lee|first2=Dong Hwan|last3=Ki|first3=Chang-Seok|last4=Lee|first4=Soo-Youn|last5=Kim|first5=Jong-Won|last6=Lee|first6=Yong-Wha|last7=Park|first7=Hyung-Doo|date=2012|title=SLC22A5 mutations in a patient with systemic primary carnitine deficiency: the first Korean case confirmed by biochemical and molecular investigation|url=https://www.ncbi.nlm.nih.gov/pubmed/23090741|journal=Annals of Clinical and Laboratory Science|volume=42|issue=4|pages=424–428|issn=1550-8080|pmid=23090741}}</ref> The symptoms and outcome of the disease can be drastically improved by replacement therapy with L-carnitine.<ref>{{Cite journal|last=Agnetti|first=Aldo|last2=Bitton|first2=Lee|last3=Tchana|first3=Bertrand|last4=Raymond|first4=Akamin|last5=Carano|first5=Nicola|date=2013-01|title=Primary carnitine deficiency dilated cardiomyopathy: 28years follow-up|url=http://linkinghub.elsevier.com/retrieve/pii/S0167527312006493|journal=International Journal of Cardiology|volume=162|issue=2|pages=e34–e35|doi=10.1016/j.ijcard.2012.05.038|issn=0167-5273|accessdate=2018-07-25}}</ref> The estimated incidence of primary carnitine deficiency in newborns is about 1 in 40,000.<ref>{{Cite journal|last=Koizumi|first=A.|last2=Nozaki|first2=J.|last3=Ohura|first3=T.|last4=Kayo|first4=T.|last5=Wada|first5=Y.|last6=Nezu|first6=J.|last7=Ohashi|first7=R.|last8=Tamai|first8=I.|last9=Shoji|first9=Y.|date=1999-11|title=Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency|url=https://www.ncbi.nlm.nih.gov/pubmed/10545605|journal=Human Molecular Genetics|volume=8|issue=12|pages=2247–2254|issn=0964-6906|pmid=10545605}}</ref>
The main [[Phenotype|phenotypical]] effect of autosomal recessive mutations, either [[Compound heterozygosity|compound heterozygous]] or [[Zygosity#Homozygous|homozygous]],<ref name=":2">{{cite journal | vauthors = 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 | title = Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death | journal = European Journal of Human Genetics | volume = 25 | issue = 6 | pages = 783–787 | date = June 2017 | pmid = 28295041 | pmc = 5477358 | doi = 10.1038/ejhg.2017.22 }}</ref> in the ''SLC22A5'' gene is [[systemic primary carnitine deficiency]],<ref name=":0" /> characterized by impaired carnitine transport, urinary carnitine wasting, low serum carnitine levels, reduced intracellular carnitine accumulation, impaired [[beta oxidation]], and [[cytosol]]ic [[fatty acid]] accumulation.<ref name=":2" /> Patients often display metabolic decompensation, [[Carnitine-acylcarnitine translocase deficiency#Presentation|hypoketotic hypoglycemia]], [[hepatic encephalopathy]], [[Reye syndrome]], and [[Sudden infant death syndrome|sudden infant death]] in their first year, followed by the later onset of [[cardiomyopathy]] or [[Skeletal muscle|skeletal]] [[myopathy]], [[Heart arrhythmia|arrhythmias]], muscle weakness, and heart failure in early childhood.<ref name=":2" /><ref>{{cite journal | vauthors = Yilmaz TF, Atay M, Toprak H, Guler S, Aralasmak A, Alkan A | title = MRI findings in encephalopathy with primary carnitine deficiency: a case report | journal = Journal of Neuroimaging | volume = 25 | issue = 2 | pages = 325–328 | date = 2014-03-10 | pmid = 24612242 | doi = 10.1111/jon.12102 | s2cid = 35640542 }}</ref><ref name=":3">{{cite journal | vauthors = Mazzini M, Tadros T, Siwik D, Joseph L, Bristow M, Qin F, Cohen R, Monahan K, Klein M, Colucci W | title = Primary carnitine deficiency and sudden death: in vivo evidence of myocardial lipid peroxidation and sulfonylation of sarcoendoplasmic reticulum calcium ATPase 2 | language = en | journal = Cardiology | volume = 120 | issue = 1 | pages = 52–8 | date = 2011 | pmid = 22116472 | doi = 10.1159/000333127 | s2cid = 207687571 }}</ref> Patients may be [[asymptomatic]], with about 70% of asymptomatic patients having a [[missense mutation]] or [[Deletion (genetics)#Effects|in-frame deletion]]; [[nonsense mutation]] frequency is increased in symptomatic patients.<ref>{{cite journal | vauthors = Yoon YA, Lee DH, Ki CS, Lee SY, Kim JW, Lee YW, Park HD | title = SLC22A5 mutations in a patient with systemic primary carnitine deficiency: the first Korean case confirmed by biochemical and molecular investigation | journal = Annals of Clinical and Laboratory Science | volume = 42 | issue = 4 | pages = 424–8 | date = 2012 | pmid = 23090741 }}</ref> The symptoms and outcome of the disease can be drastically improved by replacement therapy with L-carnitine.<ref>{{cite journal | vauthors = Agnetti A, Bitton L, Tchana B, Raymond A, Carano N | title = Primary carnitine deficiency dilated cardiomyopathy: 28 years follow-up | journal = International Journal of Cardiology | volume = 162 | issue = 2 | pages = e34–5 | date = January 2013 | pmid = 22658351 | doi = 10.1016/j.ijcard.2012.05.038 }}</ref> The estimated incidence of primary carnitine deficiency in newborns is about 1 in 40,000.<ref>{{cite journal | vauthors = 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 | title = Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency | journal = Human Molecular Genetics | volume = 8 | issue = 12 | pages = 2247–54 | date = November 1999 | pmid = 10545605 | doi = 10.1093/hmg/8.12.2247 | doi-access = free }}</ref>


== Interactions ==
== Interactions ==
SLC22A5 [[Protein–protein interaction |interacts]] with [[PDZK1]]<ref name=":1" />.
SLC22A5 [[Protein–protein interaction|interacts]] with [[PDZK1]].<ref name=":1" />


== See also ==
== See also ==
Line 24: Line 23:
== Further reading ==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
* {{cite journal | vauthors = Ascunce RR, Nayar AC, Phoon CK, Srichai MB | title = Cardiac magnetic resonance findings in a case of carnitine deficiency | journal = Texas Heart Institute Journal | volume = 40 | issue = 1 | pages = 104–5 | date = 2013 | pmid = 23468586 | pmc = 3568278 }}
{{PBB_Further_reading
* {{cite journal | vauthors = Erguven M, Yilmaz O, Koc S, Caki S, Ayhan Y, Donmez M, Dolunay G | title = A case of early diagnosed carnitine deficiency presenting with respiratory symptoms | journal = Annals of Nutrition & Metabolism | volume = 51 | issue = 4 | pages = 331–4 | date = 2007 | pmid = 17726310 | doi = 10.1159/000107675 | s2cid = 40574037 }}
| citations =
*{{cite journal | author=Silverberg MS |title=OCTNs: will the real IBD5 gene please stand up? |journal=World J. Gastroenterol. |volume=12 |issue= 23 |pages= 3678–3681 |year= 2006 |pmid= 16773684 |doi= 10.3748/wjg.v12.i23.36}}
* {{cite journal | vauthors = Hwu WL, Chien YH, Tang NL, Law LK, Lin CY, Lee NC | title = Deficiency of the carnitine transporter (OCTN2) with partial N-acetylglutamate synthase (NAGS) deficiency | journal = Journal of Inherited Metabolic Disease | volume = 30 | issue = 5 | pages = 816 | date = October 2007 | pmid = 17703373 | doi = 10.1007/s10545-007-0594-y | s2cid = 2764651 }}
*{{cite journal |vauthors=Matsuishi T, Hirata K, Terasawa K, etal |title=Successful carnitine treatment in two siblings having lipid storage myopathy with hypertrophic cardiomyopathy. |journal=Neuropediatrics |volume=16 |issue= 1 |pages= 6–12 |year= 1985 |pmid= 3974805 |doi=10.1055/s-2008-1052536 }}
* {{cite journal | vauthors = Makhseed N, Vallance HD, Potter M, Waters PJ, Wong LT, Lillquist Y, Pasquali M, Amat di San Filippo C, Longo N | title = Carnitine transporter defect due to a novel mutation in the SLC22A5 gene presenting with peripheral neuropathy | journal = Journal of Inherited Metabolic Disease | volume = 27 | issue = 6 | pages = 778–80 | date = 2004 | pmid = 15617188 | doi = 10.1023/B:BOLI.0000045837.23328.f4 | s2cid = 24144621 }}
*{{cite journal | vauthors=Wu X, Prasad PD, Leibach FH, Ganapathy V |title=cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. |journal=Biochem. Biophys. Res. Commun. |volume=246 |issue= 3 |pages= 589–95 |year= 1998 |pmid= 9618255 |doi= 10.1006/bbrc.1998.8669accessdate =2018-07-25 }}
* {{cite journal | vauthors = Kinali M, Olpin SE, Clayton PT, Daubeney PE, Mercuri E, Manzur AY, Tein I, Leonard J, Muntoni F | title = Diagnostic difficulties in a case of primary systemic carnitine deficiency with idiopathic dilated cardiomyopathy | journal = European Journal of Paediatric Neurology | volume = 8 | issue = 4 | pages = 217–9 | date = 2004 | pmid = 15261886 | doi = 10.1016/j.ejpn.2004.03.007 }}
*{{cite journal |vauthors=Shoji Y, Koizumi A, Kayo T, etal |title=Evidence for linkage of human primary systemic carnitine deficiency with D5S436: a novel gene locus on chromosome 5q. |journal=Am. J. Hum. Genet. |volume=63 |issue= 1 |pages= 101–8 |year= 1998 |pmid= 9634512 |doi=10.1086/301911 | pmc=1377235 }}
* {{cite journal | vauthors = Kinali M, Olpin SE, Clayton PT, Daubeney PE, Mercuri E, Manzur AY, Tein I, Leonard J, Muntoni F | title = Diagnostic difficulties in a case of primary systemic carnitine deficiency with idiopathic dilated cardiomyopathy | journal = European Journal of Paediatric Neurology | volume = 8 | issue = 4 | pages = 217–9 | date = 2004 | pmid = 15261886 | doi = 10.1016/j.ejpn.2004.03.007 }}
*{{cite journal |vauthors=Tamai I, Ohashi R, Nezu J, etal |title=Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. |journal=J. Biol. Chem. |volume=273 |issue= 32 |pages= 20378–82 |year= 1998 |pmid= 9685390 |doi=10.1074/jbc.273.32.20378 }}
* {{cite journal | vauthors = Silverberg MS | title = OCTNs: will the real IBD5 gene please stand up? | journal = World Journal of Gastroenterology | volume = 12 | issue = 23 | pages = 3678–81 | date = June 2006 | pmid = 16773684 | pmc = 4087460 | doi = 10.3748/wjg.v12.i23.3678 | doi-access = free }}
*{{cite journal |vauthors=Nezu J, Tamai I, Oku A, etal |title=Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. |journal=Nat. Genet. |volume=21 |issue= 1 |pages= 91–4 |year= 1999 |pmid= 9916797 |doi= 10.1038/5030 }}
* {{cite journal | vauthors = Matsuishi T, Hirata K, Terasawa K, Kato H, Yoshino M, Ohtaki E, Hirose F, Nonaka I, Sugiyama N, Ohta K | title = Successful carnitine treatment in two siblings having lipid storage myopathy with hypertrophic cardiomyopathy | journal = Neuropediatrics | volume = 16 | issue = 1 | pages = 6–12 | date = February 1985 | pmid = 3974805 | doi = 10.1055/s-2008-1052536 | s2cid = 260240244 }}
*{{cite journal |vauthors=Tang NL, Ganapathy V, Wu X, etal |title=Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency. |journal=Hum. Mol. Genet. |volume=8 |issue= 4 |pages= 655–60 |year= 1999 |pmid= 10072434 |doi=10.1093/hmg/8.4.655 }}
* {{cite journal | vauthors = Wu X, Prasad PD, Leibach FH, Ganapathy V | title = cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family | journal = Biochemical and Biophysical Research Communications | volume = 246 | issue = 3 | pages = 589–95 | date = May 1998 | pmid = 9618255 | doi = 10.1006/bbrc.1998.8669 }}
*{{cite journal |vauthors=Burwinkel B, Kreuder J, Schweitzer S, etal |title=Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality. |journal=Biochem. Biophys. Res. Commun. |volume=261 |issue= 2 |pages= 484–7 |year= 1999 |pmid= 10425211 |doi= 10.1006/bbrc.1999.1060 }}
* {{cite journal | vauthors = Shoji Y, Koizumi A, Kayo T, Ohata T, Takahashi T, Harada K, Takada G | title = Evidence for linkage of human primary systemic carnitine deficiency with D5S436: a novel gene locus on chromosome 5q | journal = American Journal of Human Genetics | volume = 63 | issue = 1 | pages = 101–8 | date = July 1998 | pmid = 9634512 | pmc = 1377235 | doi = 10.1086/301911 }}
*{{cite journal |vauthors=Wu X, Huang W, Prasad PD, etal |title=Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. |journal=J. Pharmacol. Exp. Ther. |volume=290 |issue= 3 |pages= 1482–1492 |year= 1999 |pmid= 10454528 |doi= }}
* {{cite journal | vauthors = Tamai I, Ohashi R, Nezu J, Yabuuchi H, Oku A, Shimane M, Sai Y, Tsuji A | title = Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 32 | pages = 20378–82 | date = August 1998 | pmid = 9685390 | doi = 10.1074/jbc.273.32.20378 | doi-access = free }}
*{{cite journal |vauthors=Vaz FM, Scholte HR, Ruiter J, etal |title=Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency. |journal=Hum. Genet. |volume=105 |issue= 1–2 |pages= 157–61 |year= 1999 |pmid= 10480371 |doi=10.1007/s004390051079 }}
* {{cite journal | vauthors = 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 | title = Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter | journal = Nature Genetics | volume = 21 | issue = 1 | pages = 91–4 | date = January 1999 | pmid = 9916797 | doi = 10.1038/5030 | s2cid = 20723174 }}
*{{cite journal |vauthors=Koizumi A, Nozaki J, Ohura T, etal |title=Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency |journal=Hum. Mol. Genet. |volume=8 |issue= 12 |pages= 2247–2254 |year= 1999 |pmid= 10545605 |doi=10.1093/hmg/8.12.2247 }}
* {{cite journal | vauthors = Tang NL, Ganapathy V, Wu X, Hui J, Seth P, Yuen PM, Wanders RJ, Fok TF, Hjelm NM | title = Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency | journal = Human Molecular Genetics | volume = 8 | issue = 4 | pages = 655–60 | date = April 1999 | pmid = 10072434 | doi = 10.1093/hmg/8.4.655 | doi-access = free }}
*{{cite journal |vauthors=Seth P, Wu X, Huang W, etal |title=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 |journal=J. Biol. Chem. |volume=274 |issue= 47 |pages= 33388–92 |year= 1999 |pmid= 10559218 |doi=10.1074/jbc.274.47.33388 }}
* {{cite journal | vauthors = Burwinkel B, Kreuder J, Schweitzer S, Vorgerd M, Gempel K, Gerbitz KD, Kilimann MW | title = Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality | journal = Biochemical and Biophysical Research Communications | volume = 261 | issue = 2 | pages = 484–7 | date = August 1999 | pmid = 10425211 | doi = 10.1006/bbrc.1999.1060 }}
*{{cite journal |vauthors=Mayatepek E, Nezu J, Tamai I, etal |title=Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency |journal=Hum. Mutat. |volume=15 |issue= 1 |pages= 118 |year= 2000 |pmid= 10612840 |doi= 10.1002/(SICI)1098-1004(200001)15:1<118::AID-HUMU28>3.0.CO;2-8 }}
* {{cite journal | vauthors = Wu X, Huang W, Prasad PD, Seth P, Rajan DP, Leibach FH, Chen J, Conway SJ, Ganapathy V | title = Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 290 | issue = 3 | pages = 1482–92 | date = September 1999 | pmid = 10454528 }}
*{{cite journal | vauthors=Wang Y, Kelly MA, Cowan TM, Longo N |title=A missense mutation in the OCTN2 gene associated with residual carnitine transport activity |journal=Hum. Mutat. |volume=15 |issue= 3 |pages= 238–45 |year= 2000 |pmid= 10679939 |doi= 10.1002/(SICI)1098-1004(200003)15:3<238::AID-HUMU4>3.0.CO;2-3 }}
* {{cite journal | vauthors = Vaz FM, Scholte HR, Ruiter J, Hussaarts-Odijk LM, Pereira RR, Schweitzer S, de Klerk JB, Waterham HR, Wanders RJ | title = Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency | journal = Human Genetics | volume = 105 | issue = 1–2 | pages = 157–61 | year = 1999 | pmid = 10480371 | doi = 10.1007/s004390051079 }}
*{{cite journal |vauthors=Ohashi R, Tamai I, Inano A, etal |title=Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein |journal=J. Pharmacol. Exp. Ther. |volume=302 |issue= 3 |pages= 1286–1294 |year= 2002 |pmid= 12183691 |doi= 10.1124/jpet.102.036004 }}
* {{cite journal | vauthors = 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 | title = Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency | journal = Human Molecular Genetics | volume = 8 | issue = 12 | pages = 2247–54 | date = November 1999 | pmid = 10545605 | doi = 10.1093/hmg/8.12.2247 | doi-access = free }}
*{{cite journal |vauthors=Rahbeeni Z, Vaz FM, Al-Hussein K, etal |title=Identification of two novel mutations in OCTN2 from two Saudi patients with systemic carnitine deficiency |journal=J. Inherit. Metab. Dis. |volume=25 |issue= 5 |pages= 363–9 |year= 2003 |pmid= 12408185 |doi=10.1023/A:1020143632011 }}
* {{cite journal | vauthors = Seth P, Wu X, Huang W, Leibach FH, Ganapathy V | title = 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 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 47 | pages = 33388–92 | date = November 1999 | pmid = 10559218 | doi = 10.1074/jbc.274.47.33388 | doi-access = free }}
*{{cite journal |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 }}
* {{cite journal | vauthors = Mayatepek E, Nezu J, Tamai I, Oku A, Katsura M, Shimane M, Tsuji A | title = Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency | journal = Human Mutation | volume = 15 | issue = 1 | pages = 118 | date = January 2000 | pmid = 10612840 | doi = 10.1002/(SICI)1098-1004(200001)15:1<118::AID-HUMU28>3.0.CO;2-8 | doi-access = free }}
*{{cite journal |vauthors=Elimrani I, Lahjouji K, Seidman E, etal |title=Expression and localization of organic cation/carnitine transporter OCTN2 in Caco-2 cells |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=284 |issue= 5 |pages= G863–71 |year= 2003 |pmid= 12684216 |doi= 10.1152/ajpgi.00220.2002 }}
* {{cite journal | vauthors = Wang Y, Kelly MA, Cowan TM, Longo N | title = A missense mutation in the OCTN2 gene associated with residual carnitine transport activity | journal = Human Mutation | volume = 15 | issue = 3 | pages = 238–45 | year = 2000 | pmid = 10679939 | doi = 10.1002/(SICI)1098-1004(200003)15:3<238::AID-HUMU4>3.0.CO;2-3 | s2cid = 34117262 | doi-access = free }}
*{{cite journal |vauthors=Karlic H, Lohninger A, Laschan C, etal |title=Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes |journal=J. Mol. Med. |volume=81 |issue= 7 |pages= 435–42 |year= 2004 |pmid= 12802501 |doi= 10.1007/s00109-003-0447-6 }}
* {{cite journal | vauthors = Ohashi R, Tamai I, Inano A, Katsura M, Sai Y, Nezu J, Tsuji A | title = Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 302 | issue = 3 | pages = 1286–94 | date = September 2002 | pmid = 12183691 | doi = 10.1124/jpet.102.036004 | s2cid = 1944987 }}
*{{cite journal | vauthors=Amat di San Filippo C, Wang Y, Longo N |title=Functional domains in the carnitine transporter OCTN2, defective in primary carnitine deficiency |journal=J. Biol. Chem. |volume=278 |issue= 48 |pages= 47776–84 |year= 2004 |pmid= 14506273 |doi= 10.1074/jbc.M307911200 }}
* {{cite journal | vauthors = Rahbeeni Z, Vaz FM, Al-Hussein K, Bucknall MP, Ruiter J, Wanders RJ, Rashed MS | title = Identification of two novel mutations in OCTN2 from two Saudi patients with systemic carnitine deficiency | journal = Journal of Inherited Metabolic Disease | volume = 25 | issue = 5 | pages = 363–9 | date = September 2002 | pmid = 12408185 | doi = 10.1023/A:1020143632011 | s2cid = 25824831 }}
* {{cite journal | vauthors = Elimrani I, Lahjouji K, Seidman E, Roy MJ, Mitchell GA, Qureshi I | title = Expression and localization of organic cation/carnitine transporter OCTN2 in Caco-2 cells | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 284 | issue = 5 | pages = G863–71 | date = May 2003 | pmid = 12684216 | doi = 10.1152/ajpgi.00220.2002 }}
}}
* {{cite journal | vauthors = Karlic H, Lohninger A, Laschan C, Lapin A, Böhmer F, Huemer M, Guthann E, Rappold E, Pfeilstöcker M | title = Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes | journal = Journal of Molecular Medicine | volume = 81 | issue = 7 | pages = 435–42 | date = July 2003 | pmid = 12802501 | doi = 10.1007/s00109-003-0447-6 | s2cid = 10992930 }}
* {{cite journal | vauthors = Amat di San Filippo C, Wang Y, Longo N | title = Functional domains in the carnitine transporter OCTN2, defective in primary carnitine deficiency | journal = The Journal of Biological Chemistry | volume = 278 | issue = 48 | pages = 47776–84 | date = November 2003 | pmid = 14506273 | doi = 10.1074/jbc.M307911200 | doi-access = free }}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|SLC22A5+protein,+human}}
* {{MeshName|SLC22A5+protein,+human}}
* [http://www.arup.utah.edu/database/OCTN2/OCTN2_welcome.php/ Primary Carnitine Deficiency (OCTN2 database)]
* [http://www.arup.utah.edu/database/OCTN2/OCTN2_welcome.php/ Primary Carnitine Deficiency (OCTN2 database)]
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{{Membrane transport proteins}}
{{Membrane transport proteins}}

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[[Category:Solute carrier family]]
[[Category:Solute carrier family]]
[[Category:Amphetamine]]
[[Category:Amphetamine]]

{{Portal bar | Mitochondria | Gene Wiki}}

Latest revision as of 13:22, 7 September 2023

SLC22A5
Identifiers
AliasesSLC22A5, CDSP, OCTN2, solute carrier family 22 member 5
External IDsOMIM: 603377; MGI: 1329012; HomoloGene: 68295; GeneCards: SLC22A5; OMA:SLC22A5 - orthologs
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 MbChr 11: 53.76 – 53.78 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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]

Structure[edit]

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[edit]

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[edit]

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[edit]

SLC22A5 interacts with PDZK1.[11]

See also[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000197375 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b c "Entrez Gene: SLC22A5 solute carrier family 22 (organic cation transporter), member 5". Retrieved 2018-07-25.
  6. ^ a b c d 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. ^ a b 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. ^ a b "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[edit]

External links[edit]

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

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