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Carnitine transport: Pathophysiology and metabolism of known molecular defects
Abstract
Summary: Early‐onset dilatative and/or hypertrophic cardiomyopathy with episodic hypoglycaemic coma and very low serum and tissue concentrations of carnitine should alert the clinician to the probability of the plasmalemmal high‐affinity carnitine transporter defect. The diagnosis can be established by demonstration of impaired carnitine uptake in cultured skin fibroblasts or lymphoblasts and confirmed by mutation analysis of the human OCTN2 gene in the affected child and obligate heterozygote parents. The institution of high‐dose oral carnitine supplementation reverses the pathology in this otherwise lethal autosomal recessive disease of childhood, and carnitine therapy from birth in prospectively screened siblings may altogether prevent the development of the clinical phenotype. Heterozygotes may be at risk for cardiomyopathy in later adult life, particularly in the presence of additional risk factors such as hypertension and competitive pharmacological agents. OCTN2 belongs to a family of organic cation/carnitine transporters that function primarily in the elimination of cationic drugs and other xenobiotics in kidney, intestine, liver and placenta. The high‐ and low‐affinity human carnitine transporters, OCTN2 and OCTN1, are multifunctional polyspecific organic cation transporters; therefore, defects in these transporters may have widespread implications for the absorption and/or elimination of a number of key pharmacological agents such as cephalosporins, verapamil, quinidine and valproic acid. A third organic/cation carnitine transporter with high specificity for carnitine, Octn3, has been clonedin mice. The juvenile visceral steatosis (jvs) mouse serves as an excellent clinical, biochemical and molecular model for the high‐affinity carnitine transporter OCTN2 defect and is due to a spontaneous point mutation in the murine Octn2 gene on mouse chromosome 11, which is syntenic to the human locus at 5q31 that harbours the human OCTN2 gene.
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“More direct evidence linking carnitine imbalance to mitochondrial dysfunction comes from the juvenile visceral steatosis (jvs) mice, a genetic model of primary carnitine deficiency.”
From Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control (2009) · cites this paper as [42]
In the citing paper
“These animals harbor a spontaneous point mutation in OCTN2, resulting in severely depleted tissue carnitine content and marked derangements in mitochondrial genesis and morphology, as well as whole body lipid and energy metabolism (41,42).”
From Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control (2009) · cites this paper as [42]
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Metadata
- Authors
- Tein, I.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Tein, I.
- ORCID
- Tein, I.
- Venue
- Journal of Inherited Metabolic Disease
- Publisher
- Wiley
- Published
- 2003-03
- Volume
- 26
- Issue
- 2-3
- Pages
- 147-169
- ISSN
- 0141-8955 (ISSN-L)
- 1573-2665
- OpenAlex
- W1569055531
- Cited by
- 140
- References
- 124
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 6 · 2013: 6 · 2012: 11
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Inherited Metabolic Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- carnitine transport, OCTN2, OCTN1, carnitine deficiency, cardiomyopathy, hypoglycemic coma, organic cation transporters, carnitine supplementation, autosomal recessive inheritance, drug transport, cephalosporins, verapamil, quinidine, valproic acid, genotype-phenotype correlation
- MeSH terms
- Solute Carrier Family 22 Member 5, Animals, Biological Transport, Carnitine, Carrier Proteins, Disease Models, Animal, Humans, Membrane Proteins, Mutation, Valproic Acid, Membrane Transport Proteins, Organic Cation Transport Proteins, Symporters, Mice, Chemical and Drug Induced Liver Injury
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