Evidence for Linkage of Human Primary Systemic Carnitine Deficiency with D5S436: A Novel Gene Locus on Chromosome 5q

Shoji, Yutaka; Koizumi, Akio; Kayo, Tsuyoshi; Ohata, Tomoaki; Takahashi, Tsutomu; Harada, Kenji; Takada, Goro

doi:10.1086/301911

Cited by 48 publications

(21 citation statements)

References 13 publications

(14 reference statements)

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“…The gene for primary carnitine deficiency encodes a functional carnitine transporter named OCTN2 (SLC22A5; MIM# 603377) [Wu et al, 1998;Tamai et al, 1998] which maps to chromosome 5q31.1-32 [Shoji et al, 1998;Wu et al, 1998]. Mutations in this gene have been reported in a few patients with primary carnitine deficiency [Nezu et al, 1999;Wang et al, 1999;Tang et al, 1999;Burwinkel et al, 1999], most of whom presented early in life with a severe metabolic decompensation.…”

Section: Introductionmentioning

confidence: 99%

A missense mutation in the OCTN2 gene associated with residual carnitine transport activity

et al. 2000

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Section: Introductionmentioning

confidence: 99%

A missense mutation in the OCTN2 gene associated with residual carnitine transport activity

et al. 2000

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“…6). Although the responsible loci have been mapped in both human 7 and mouse 8 , the underlying gene has not yet been identified. Recently, we cloned and analysed the function of a novel transporter protein termed OCTN2 (ref.…”

mentioning

confidence: 99%

Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter

Nezu¹,

Tamai

Oku³

et al. 1999

Nat Genet

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507

317

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Primary systemic carnitine deficiency (SCD; OMIM 212140) is an autosomal recessive disorder characterized by progressive cardiomyopathy, skeletal myopathy, hypoglycaemia and hyperammonaemia. SCD has also been linked to sudden infant death syndrome. Membrane-physiological studies have suggested a defect of the carnitine transport system in the plasma membrane in SCD patients and in the mouse model, juvenile visceral steatosis. Although the responsible loci have been mapped in both human and mouse, the underlying gene has not yet been identified. Recently, we cloned and analysed the function of a novel transporter protein termed OCTN2. Our observation that OCTN2 has the ability to transport carnitine in a sodium-dependent manner prompted us to search for mutations in the gene encoding OCTN2, SLC22A5. Initially, we analysed the mouse gene and found a missense mutation in Slc22a5 in jvs mice. Biochemical analysis revealed that this mutation abrogates carnitine transport. Subsequent analysis of the human gene identified four mutations in three SCD pedigrees. Affected individuals in one family were homozygous for the deletion of a 113-bp region containing the start codon. In the second pedigree, the affected individual was shown to be a compound heterozygote for two mutations that cause a frameshift and a premature stop codon, respectively. In an affected individual belonging to a third family, we found a homozygous splice-site mutation also resulting in a premature stop codon. These mutations provide the first evidence that loss of OCTN2 function causes SCD.

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“…The gene for primary carnitine deficiency encodes a functional carnitine transporter named OCTN2 (3,4) that maps to chromosome 5q31.1-32 (3,5). OCTN2 is a novel organic cation transporter and operates a sodium-dependent transport of carnitine.…”

mentioning

confidence: 99%

Abnormal Sodium Stimulation of Carnitine Transport in Primary Carnitine Deficiency

Wang

Meadows

Longo

2000

Journal of Biological Chemistry

104

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Primary carnitine deficiency is an autosomal recessive disorder of fatty acid oxidation characterized by hypoketotic hypoglycemia and skeletal and cardiac myopathy. It is caused by mutations in the sodium-dependent carnitine cotransporter OCTN2. The majority of natural mutations identified in this and other Na ؉ /solute symporters introduce premature termination codons or impair insertion of the mutant transporter on the plasma membrane. Here we report that a missense mutation (E452K) identified in one patient with primary carnitine deficiency did not affect membrane targeting, as assessed with confocal microscopy of transporters tagged with the green fluorescent protein, but reduced carnitine transport by impairing sodium stimulation of carnitine transport. The natural mutation increased the concentration of sodium required to half-maximally stimulate carnitine transport (K Na ) from the physiological value of 11.6 to 187 mM. Substitution of Glu 452 with glutamine (E452Q), aspartate (E452D), or alanine (E452A) caused intermediate increases in the K Na . Carnitine transport decreased exponentially with increased K Na . The E452K mutation is the first natural mutation in a mammalian cotransporter affecting sodium-coupled solute transfer and identifies a novel domain of the OCTN2 cotransporter involved in transmembrane sodium/solute transfer.

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Evidence for Linkage of Human Primary Systemic Carnitine Deficiency with D5S436: A Novel Gene Locus on Chromosome 5q

Cited by 48 publications

References 13 publications

A missense mutation in the OCTN2 gene associated with residual carnitine transport activity

A missense mutation in the OCTN2 gene associated with residual carnitine transport activity

Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter

Abnormal Sodium Stimulation of Carnitine Transport in Primary Carnitine Deficiency

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