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Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter.
Nat Genet. 1999 Jan; 21(1):91-4.NGen

Abstract

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.

Authors+Show Affiliations

Chugai Research Institute for Molecular Medicine, Ibaraki, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9916797

Citation

Nezu, J, et al. "Primary Systemic Carnitine Deficiency Is Caused By Mutations in a Gene Encoding Sodium Ion-dependent Carnitine Transporter." Nature Genetics, vol. 21, no. 1, 1999, pp. 91-4.
Nezu J, Tamai I, Oku A, et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet. 1999;21(1):91-4.
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. (1999). Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nature Genetics, 21(1), 91-4.
Nezu J, et al. Primary Systemic Carnitine Deficiency Is Caused By Mutations in a Gene Encoding Sodium Ion-dependent Carnitine Transporter. Nat Genet. 1999;21(1):91-4. PubMed PMID: 9916797.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. AU - Nezu,J, AU - Tamai,I, AU - Oku,A, AU - Ohashi,R, AU - Yabuuchi,H, AU - Hashimoto,N, AU - Nikaido,H, AU - Sai,Y, AU - Koizumi,A, AU - Shoji,Y, AU - Takada,G, AU - Matsuishi,T, AU - Yoshino,M, AU - Kato,H, AU - Ohura,T, AU - Tsujimoto,G, AU - Hayakawa,J, AU - Shimane,M, AU - Tsuji,A, PY - 1999/1/23/pubmed PY - 2001/3/23/medline PY - 1999/1/23/entrez SP - 91 EP - 4 JF - Nature genetics JO - Nat Genet VL - 21 IS - 1 N2 - 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. SN - 1061-4036 UR - https://www.unboundmedicine.com/medline/citation/9916797/Primary_systemic_carnitine_deficiency_is_caused_by_mutations_in_a_gene_encoding_sodium_ion_dependent_carnitine_transporter_ L2 - https://doi.org/10.1038/5030 DB - PRIME DP - Unbound Medicine ER -