Mutations of OCTN2, an Organic Cation/Carnitine Transporter, Lead to Deficient Cellular Carnitine Uptake in Primary Carnitine Deficiency

Tang, Nelson L.S.; Ganapathy, Vadivel; Wu, Xiang; Hui, Joannie; Seth, Pankaj; Yuen, Pong Mo; Fok, Tai-fai; Hjelm, N M

doi:10.1093/hmg/8.4.655

Cited by 140 publications

(83 citation statements)

References 23 publications

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“…A defect in carnitine transport across the cell membrane had been established as the etiology of this disease. Research from our group and others showed that mutations in OCTN2 gene (SLC22A5; MIM# 603377), which encodes a plasma membrane carnitine transporter, were the molecular defect in PCD patients (Lamhonwah et al, 1998;Nezu et al, 1999;Tang et al, 1999;Wang et al, 1999).…”

Section: Introductionmentioning

confidence: 92%

“…The recurrent mutation S467C was found in PCD patients in the Akita Japanese population and was also believed to be an ancient mutation . For other examples, the W132X and W283C were found recurrent in East Asian populations Tang et al, 1999). In addition, R282X was common in Caucasian (Burwinkel et al, 1999;Vaz et al, 1999;Wang et al, 1999).…”

Section: Introductionmentioning

confidence: 98%

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A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients

et al. 2002

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Mutations in the SLC22A5 gene, which encodes for the plasma membrane carnitine transporter OCTN2, cause primary carnitine deficiency (PCD). After our first report of OCTN2 mutations in Chinese, three more Chinese PCD patients were identified. The parents of these families were non-consanguineous and these families were unrelated. Two novel truncating mutations were found: R254X, a single-base mutation at cDNA position 981 (c.981C>T); and Y387X (c.1382T>G). Two probands, one each from Taiwan and Macau, were homozygous for R254X. The other proband from Taiwan carried both R254X and Y387X. Two additional heterozygote carriers of R254X were also identified among 250 control samples, while none was detected for Y387X. The population carrier rate for R254X would be about 1 in 125. Haplotypes of R254X alleles were examined and patients homozygous for R254X were also homozygous for the same haplotype of intragenic and microsatellites markers. Analysis of population frequencies of haplotypes revealed that the chance of 4 chromosomes having arisen as independent events was 0.016. We conclude that R254X is probably a founder mutation in Chinese. Other previously reported mutations found in the Japanese population were also screening in 250 control samples but no carrier was identified, indicating that they were either very rare or not present in Southern Chinese.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 98%

A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients

et al. 2002

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“…The latter was shown to be a physiologically essential high-affinity Na ϩ -dependent carnitine transporter by the demonstration that mutations found in SCD patients and jvs mice cause functional alteration of OCTN2 (9,12). Other similar mutations in OCTN2 related to SCD have been reported (13)(14)(15)(16)(17)(18)(19)(20). Interestingly, OCTN1 and -2 in human transported organic cations such as tetraethylammonium (TEA) as well as acylcarnitines (11,(21)(22)(23), suggesting that OCTNs may be important for the transport of xenobiotics and acylated carnitine as well as carnitine itself.…”

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confidence: 95%

Molecular and Functional Characterization of Organic Cation/Carnitine Transporter Family in Mice

Tamai¹,

Ohashi²,

Nezu³

et al. 2000

Journal of Biological Chemistry

272

336

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Carnitine is essential for ␤-oxidation of fatty acids, and a defect of cell membrane transport of carnitine leads to fatal systemic carnitine deficiency. We have already shown that a defect of the organic cation/carnitine transporter OCTN2 is a primary cause of systemic carnitine deficiency. In the present study, we further isolated and characterized new members of the OCTN family, OCTN1 and -3, in mice. All three members were expressed commonly in kidney, and OCTN1 and -2 were also expressed in various tissues, whereas OCTN3 was characterized by predominant expression in testis. When their cDNAs were transfected into HEK293 cells, the cells exhibited transport activity for carnitine and/or the organic cation tetraethylammonium (TEA). Carnitine transport by OCTN1 and OCTN2 was Na ؉ -dependent, whereas that by OCTN3 was Na ؉ -independent. TEA was transported by OCTN1 and OCTN2 but not by OCTN3. The relative uptake activity ratios of carnitine to TEA were 1.78, 11.3, and 746 for OCTN1, -2, and -3, respectively, suggesting high specificity of OCTN3 for carnitine and significantly lower carnitine transport activity of OCTN1. Thus, OCTN3 is unique in its limited tissue distribution and Na ؉ -independent carnitine transport, whereas OCTN1 efficiently transported TEA with minimal expression of carnitine transport activity and may have a different role from other members of the OCTN family.

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“…OCTN2 gene is located on chromosome 5q31 with ten exons encoding a 557-amino acid transmembrane protein consisting of 12 transmembrane domains and one ATP-binding domain and predicted molecular mass of 63 kDa (Saito et al 2002;Wu et al 1999). More than 90 mutations have been identified up to date (Amat di San Filippo C et al 2006aFilippo C et al , b, 2008Burwinkel et al 1999;Cederbaum et al 2002;Dobrowolski et al 2005;Koizumi et al 1999;Lamhonwah et al 2002;Li et al 2010;Makhseed et al 2004;Mayatepek et al 2000;Nezu et al 1999;Rahbeeni et al 2002;Spiekerkoetter et al 2003;Tang et al 1999;Vaz et al 1999;Wang et al 1999Wang et al , 2000aWang et al , b, 2001.…”

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confidence: 99%

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

et al. 2011

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Primary systemic carnitine deficiency (SCD) is an autosomal recessive disorder caused by defective cellular carnitine transport. Patients usually present with predominant metabolic or cardiac manifestations. SCD is caused by mutations in the organic cation/carnitine transporter OCTN2 (SLC22A5) gene. Mutation analysis of SLC22A5 gene was carried out in eight Turkish patients from six families. Six patients presented with signs and symptoms of heart failure, cardiomyopathy, and low plasma carnitine levels, five of them with concurrent anemia. A patient with dilated cardiomyopathy had also facial dysmorphia, microcephaly, and developmental delay. Tandem MS analyses in siblings of the patients revealed two more cases with low plasma carnitine levels. SCD diagnosis was confirmed in these two cases by mutation screening. These two cases were asymptomatic but echocardiography revealed left ventricular dilatation in one of them. Carnitine treatment was started before the systemic signs and symptoms developed in these patients. Mean value of serum carnitine levels of the patients was 2.63 AE 1.92 mmol/L at the time of diagnosis. After 1 year of treatment, carnitine values increased to 16.62 AE 5.11 (p < 0.001) and all responded to carnitine supplementation clinically.

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Mutations of OCTN2, an Organic Cation/Carnitine Transporter, Lead to Deficient Cellular Carnitine Uptake in Primary Carnitine Deficiency

Cited by 140 publications

References 23 publications

A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients

A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients

Molecular and Functional Characterization of Organic Cation/Carnitine Transporter Family in Mice

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

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