title: A mutation in the SEPN1 selenocysteine redefinition element (SRE) reduces selenocysteine incorporation and leads to SEPN1-related myopathy.
abstract: Mutations in SEPN1 result in a spectrum of early-onset muscle disorders referred to as SEPN1-related myopathy. The SEPN1 gene encodes selenoprotein N (SelN), which contains the amino acid selenocysteine (Sec). Incorporation of Sec occurs due to redefinition of a UGA codon during translation. Efficient insertion requires a Sec insertion sequence (SECIS) in the 3'UTR and, for at least a subset of selenoprotein genes, a Sec redefinition element (SRE) located adjacent to the UGA codon. We report the effect of three novel and one previously reported point mutation in the SelN SRE element on Sec insertion efficiency. Notably, the previously reported mutation c.1397G>A (p.R466Q), which weakens the secondary structure of the SRE element, reduces Sec insertion efficiency and SelN RNA levels. Muscle from patients with this mutation have negligible levels of SelN protein. This data highlights the importance of the SRE element during SelN expression and illustrates a novel molecular mechanism by which point mutations may lead to SEPN1-related myopathy.
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Baijayanta
authors.initials: B
authors.lastname: Maiti
authors.forename: Sandrine
authors.initials: S
authors.lastname: Arbogast
authors.forename: Valérie
authors.initials: V
authors.lastname: Allamand
authors.forename: Mark W
authors.initials: MW
authors.lastname: Moyle
authors.forename: Christine B
authors.initials: CB
authors.lastname: Anderson
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreiro
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
authors.forename: Michael T
authors.initials: MT
authors.lastname: Howard
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D018388:Codon, Terminator / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D049409:Luciferases, Firefly / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017279:Selenocysteine / Q000378:metabolism*; D051140:Selenoproteins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D018388:Codon, Terminator; D009124:Muscle Proteins; D011993:Recombinant Fusion Proteins; C435489:SELENON protein, human; D051140:Selenoproteins; D017279:Selenocysteine; D049409:Luciferases, Firefly