A mutation creating an upstream translation initiation codon in SLC22A5 5’UTR is a frequent cause of primary carnitine deficiency


Presented By:

Sacha Ferdinandusse, Heleen te Brinke, Jos P.N. Ruiter, Janet Haasjes, Wendy Oostheim, Henk van
Lenthe, Lodewijk IJlst, Merel S. Ebberink, Ronald J.A. Wanders, Frédéric M. Vaz, Hans R. Waterham
Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam,
Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Corresponding author: Sacha Ferdinandusse, PhD, Email: S.Ferdinandusse@amc.nl, Phone: +31 20 5662485

Primary carnitine deficiency is caused by a defect in the active cellular uptake of carnitine by the Na+- dependent organic cation transporter novel 2 (OCTN2). This defect results in low serum and tissue carnitine levels and impairs β-oxidation of long-chain fatty acids. Clinical presentation is highly variable from very severe to very mild. Diagnostic yield of genetic testing for primary carnitine deficiency is relatively low and it has long been suspected that disease-causing variants are missed.

We Sanger sequenced the 5’ untranslated region (UTR) of the SLC22A5 gene in individuals with possible primary carnitine deficiency in whom no or only one mutant allele had been found. We characterized a novel 5’-UTR variant by expression studies with reporter constructs in HeLa cells and by carnitine transport measurements in fibroblasts using a newly developed sensitive assay based on tandem mass spectrometry.

We identified and characterized a novel 5’UTR variant in SLC22A5. This variant, which was identified in 57 individuals of our cohort of 236, introduces a functional upstream out of frame translation initiation codon. We show that this codon suppresses translation from the wild-type ATG of SLC22A5, resulting in
reduced OCTN2 protein levels and concomitantly lower OCTN2 transport activity.

Mutations in the 5’UTR has been described as cause of disease for different diseases and is now also found to cause primary carnitine deficiency. With an allele frequency of 24.2% this 5’UTR variant is the most frequent cause of primary carnitine deficiency in our cohort and may explain other reported cases with an incomplete genetic diagnosis. Individuals carrying this variant should be clinically re-evaluated and monitored to determine if this variant has clinical consequences.

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