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

Standard

A mutation creating an upstream translation initiation codon in SLC22A5 5'UTR is a frequent cause of primary carnitine deficiency. / Ferdinandusse, Sacha ; te Brinke, Heleen; Ruiter, Jos P. N. et al.
In: Human mutation, Vol. 40, No. 10, 2019, p. 1899-1904.

Research output: Contribution to journal › Article › Academic › peer-review

BibTeX

@article{41f83986d6d748a1ae299798443c3e5e,

title = "A mutation creating an upstream translation initiation codon in SLC22A5 5'UTR is a frequent cause of primary carnitine deficiency",

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.",

author = "Sacha Ferdinandusse and {te Brinke}, Heleen and Ruiter, {Jos P. N.} and Janet Haasjes and Wendy Oostheim and {van Lenthe}, Henk and Lodewijk IJlst and Ebberink, {Merel S.} and Wanders, {Ronald J. A.} and Vaz, {Fr{\'e}d{\'e}ric M.} and Waterham, {Hans R.}",

year = "2019",

doi = "10.1002/humu.23839",

language = "English",

volume = "40",

pages = "1899--1904",

journal = "Human mutation",

issn = "1059-7794",

publisher = "Wiley-Liss Inc.",

number = "10",

}

RIS

TY - JOUR

T1 - A mutation creating an upstream translation initiation codon in SLC22A5 5'UTR is a frequent cause of primary carnitine deficiency

AU - Ferdinandusse, Sacha

AU - te Brinke, Heleen

AU - Ruiter, Jos P. N.

AU - Haasjes, Janet

AU - Oostheim, Wendy

AU - van Lenthe, Henk

AU - IJlst, Lodewijk

AU - Ebberink, Merel S.

AU - Wanders, Ronald J. A.

AU - Vaz, Frédéric M.

AU - Waterham, Hans R.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85072718264&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31187905

U2 - 10.1002/humu.23839

DO - 10.1002/humu.23839

M3 - Article

C2 - 31187905

VL - 40

SP - 1899

EP - 1904

JO - Human mutation

JF - Human mutation

SN - 1059-7794

IS - 10

ER -

ID: 7043434

Generic Portal