A mutation creating an out‐of‐frame alternative translation initiation site in the GRHPR 5′UTR causing primary hyperoxaluria type II. (26th December 2014)

• Record Type: Journal Article
• Authors: Fu, Y.; Rope, R.; Fargue, S.; Cohen, H.T.; Holmes, R.P.; Cohen, D.M.
• Is Part Of: Clinical genetics. Volume 88:Number 5(2015:Nov.)
• Page Start: 494
• Page End: 498
• Publication Date: 2014-12-26
• Subjects: Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.12541
• Languages: English
• ISSNs: 0009-9163

Abstract

<abstract abstract-type="main" id="cge12541-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p id="cge12541-para-0001">Primary hyperoxaluria type II is a recessive genetic disorder caused by mutations in the <italic>GRHPR</italic> 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 <italic>GRHPR</italic> affecting Gln²³², 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 <italic>cis</italic>, on the opposite allele, and introduce – immediately upstream of the canonical translation initiation site – a novel out‐of‐frame translational start site. <italic>In vitro</italic> studies using the <italic>GRHPR</italic> 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 <italic>GRHPR</italic> proximal promoter. This latter mechanism may be underappreciated in general; reports of clinically significant functional variation of this type are extremely rare.</p> </abstract>