A mutation creating an upstream translation initiation codon in SLC22A5 5'UTR is a frequent cause of primary carnitine deficiency.
Hum Mutat
; 40(10): 1899-1904, 2019 10.
Article
in En
| MEDLINE
| ID: mdl-31187905
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carnitine
/
Codon, Initiator
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Genetic Predisposition to Disease
/
5' Untranslated Regions
/
Hyperammonemia
/
Solute Carrier Family 22 Member 5
/
Muscular Diseases
/
Mutation
/
Cardiomyopathies
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Hum Mutat
Journal subject:
GENETICA MEDICA
Year:
2019
Document type:
Article
Affiliation country: