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

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.

Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2−/−) mice

“…Several pairs of OCTN2 +/-heterozygous males and females were mated to obtain homozygous OCTN2 -/-mice. Homozygous OCTN2 -/-mice in the litter were genotyped using a RFLP based method; [9] they can also be identified by 4-5 weeks of age when small size and weakness become apparent. Wild type (OCTN2 +/+ ) and homozygous (OCTN2 -/-) pups were sacrificed at 4 weeks of age to identify any GI tract pathology.…”

“…At 3-weeks of age, the body weight of the OCTN2 -/-mice is about 50% compared to that of age-matched wild type mice. Furthermore, OCTN2 -/-mice develop enlarged fatty liver with steatosis of other organs and hypertrophic cardiomyopathy which led to its original designation as the juvenile visceral steatosis (jvs) mouse [9] (Fig-1).…”

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

“…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.…”

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

“…35 Ganapathy et al 36 demonstrated that many ß-lactam antibiotics that are not recognized by OCTN2 are good substrates for the H + -coupled PEPT1 and PEPT2, and found that cephaloridine, cefoselis, cefepime and cefluprenam significantly inhibited OCTN2-mediated transport of carnitine. These antibiotics possess a quaternary nitrogen, as does carnitine.…”