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A mutation creating an upstream translation initiation codon in SLC22A5 5′UTR is a frequent cause of primary carnitine deficiency
Author(s) -
Ferdinandusse Sacha,
te Brinke Heleen,
Ruiter Jos P.N.,
Haasjes Janet,
Oostheim Wendy,
Lenthe Henk,
IJlst Lodewijk,
Ebberink Merel S.,
Wanders Ronald J.A.,
Vaz Frédéric M.,
Waterham Hans R.
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23839
Subject(s) - carnitine , biology , sanger sequencing , untranslated region , five prime untranslated region , genetics , mutation , translation (biology) , three prime untranslated region , translational regulation , allele , start codon , microbiology and biotechnology , messenger rna , gene , biochemistry
Primary carnitine deficiency is caused by a defect in the active cellular uptake of carnitine by Na + ‐dependent organic cation transporter novel 2 (OCTN2). Genetic diagnostic yield for this metabolic disorder has been relatively low, suggesting that disease‐causing variants are missed. We Sanger sequenced the 5′ untranslated region (UTR) of SLC22A5 in individuals with possible primary carnitine deficiency in whom no or only one mutant allele had been found. We identified a novel 5′‐UTR c.‐149G>A variant which we characterized 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. This variant, which we identified in 57 of 236 individuals of our cohort, introduces a functional upstream out‐of‐frame translation initiation codon. We show that the codon suppresses translation from the wild‐type ATG of SLC22A5 , resulting in reduced OCTN2 protein levels and concomitantly lower transport activity. With an allele frequency of 24.2% the c.‐149G>A 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.