Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency: Lack of genotype-phenotype correlation

Primary carnitine deficiency is an autosomal recessive disorder of fatty ac id oxidation caused by defective carnitine transport, This disease is cause d by mutations in the novel organic cation transporter OCTN2 (SLC22A5 gene) , The disease can present early in life with hypoketotic hypoglycemia or la ter in lift: with skeletal myopathy or cardiomyopathy, To determine whether the variation in phenotypic severity is due to mutations retaining residua l function, we extended mutational analysis of OCTN2 to four additional Eur opean families with primary carnitine deficiency, Three patients were homoz ygous for novel missense mutations (R169W, G242V, A301D), The fourth patien t was compound heterozygous fur R169W and W351R substitutions, Stable expre ssion of all the mutations in CHO cells confirmed that all mutations abolis hed carnitine transport, with the exception of the A301D mutation in which residual carnitine transport was 2-3% of the value measured in cells expres sing the normal OCTN2 cDNA, Analysis of the patients characterized in molec ular derail by our laboratory failed to indicate a correlation between resi dual carnitine transport and severity of the phenotype or age at presentati on, Hum Mutat 16:401-407, 2000, (C) 2000 Wiley-Liss, Inc.