title: A mutation creating an out-of-frame alternative translation initiation site in the GRHPR 5'UTR causing primary hyperoxaluria type II.
abstract: Primary hyperoxaluria type II is a recessive genetic disorder caused by mutations in the GRHPR gene. Although several dozen mutations have been described, all affect coding or transcript splicing. A man suspected of having primary hyperoxaluria type II was heterozygous for a novel single-nucleotide deletion (c.694delC) in GRHPR affecting Gln(232) , which introduced a pre-mature termination (p.Gln232Argfs*3). Two 5'untranslated region (UTR) variants of unknown significance were also noted. We show that these two variants occur in cis, on the opposite allele, and introduce - immediately upstream of the canonical translation initiation site - a novel out-of-frame translational start site. In vitro studies using the GRHPR 5'UTR fused to a luciferase reporter show that the variant start site pre-empted initiation at the canonical translational start site, and this was corroborated within the broader context of 1.3 kb of the GRHPR proximal promoter. This latter mechanism may be underappreciated in general; reports of clinically significant functional variation of this type are extremely rare.
authors.affiliation: Division of Nephrology & Hypertension, Oregon Health & Science University and the Portland VA Medical Center, Portland, OR, 97239, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Division of Nephrology & Hypertension, Oregon Health & Science University and the Portland VA Medical Center, Portland, OR, 97239, USA.
authors.forename: R
authors.initials: R
authors.lastname: Rope
authors.affiliation: Department of Urology, University of Alabama School of Medicine, Birmingham, AL, 35294, USA.
authors.forename: S
authors.initials: S
authors.lastname: Fargue
authors.affiliation: Renal Section, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: H T
authors.initials: HT
authors.lastname: Cohen
authors.affiliation: Department of Urology, University of Alabama School of Medicine, Birmingham, AL, 35294, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Holmes
authors.affiliation: Division of Nephrology & Hypertension, Oregon Health & Science University and the Portland VA Medical Center, Portland, OR, 97239, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Cohen
mesh_terms: D020121:5' Untranslated Regions; D000328:Adult; D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D018388:Codon, Terminator; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010442:Peptide Chain Initiation, Translational; D017384:Sequence Deletion
chemical_list: D020121:5' Untranslated Regions; D018388:Codon, Terminator; D000429:Alcohol Oxidoreductases; C020830:glyoxylate reductase
keywords: human; hyperoxaluria; mutation; translation