Positional cloning of carnitine transporter gene and its contribution on hypoglycemia.

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Juvenile Visceral Steatosis (JVS) mouse, which we reported in 1991, serves as an animal model of primary carnitine deficiency. Because this mouse is suffered from severe hypoglycemia, we analyzed the cause and mechanism The summary of the results is as follows ;1. Assay of carnitine transport activityWe have conducted a kinetic analysis using fibroblasts derived from normal, heterozygous, and homozygous JVS mice and found that the high-affinity carnitine transporter, which shows NaィイD1+ィエD1 dependency, is defective in homozygous JVS mice. Moreover, a gene dose-dependent decrease of carnitine transport activity was found in heterozygous JVS mice.2. Analysis of candidate geneAs a human OCTN2 gene encoding a sodium-dependent carnitine cotranspoter was isolated, we isolated the mouse octn2 gene and screened for its mutation in the JVS mouse. DNA sequencing analysis disclosed a missense mutation from CTG (Leu) to CGG (Arg) at codon 352 located within the sixth transmembrane domain of octn2. This amino acid replacement possibly causes the conformational change of the protein that leads to dysfunction of the gene product.3. Analysis of hypoglycemiaThe glucose level of JVS mouse at ad lib feeding was lower than that of normal control. After the prolonged starvation, the glucose level of JVS mouse was significantly decreased at 60 hours in comparison with normal control. The insulin level was not changed between JVS and normal control mouse. The levels of pyruvate and lactate were decreased. This decreased was thought as a cause of hypoglycemia.