Incorporation of the 21st amino acid, selenocysteine, into proteins is specified in all three domains of life by dynamic translational redefinition of UGA codons. In eukarya and archaea, selenocysteine insertion requires a cis-acting selenocysteine insertion sequence (SECIS) usually located in the 3'UTR of selenoprotein mRNAs. Here we present comparative sequence analysis and experimental data supporting the presence of a second stop codon redefinition element located adjacent to a selenocysteine-encoding UGA codon in the eukaryal gene, SEPN1. This element is sufficient to stimulate high-level (6%) translational redefinition of the SEPN1 UGA codon in human cells. Readthrough levels further increased to 12% when tested in the presence of the SEPN1 3'UTR SECIS. Directed mutagenesis and phylogeny of the sequence context strongly supports the importance of a stem loop starting six nucleotides 3' of the UGA codon. Sequences capable of forming strong RNA structures were also identified 3' adjacent to, or near, selenocysteine-encoding UGA codons in the Sps2, SelH, SelO, and SelT selenoprotein genes.
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http://dx.doi.org/10.1038/sj.emboj.7600642 | DOI Listing |
Biomedica
December 2024
Grupo de Inmunodeficiencias Primarias, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
Introduction: Common variable immunodeficiency is a diagnosis of exclusion in immunodeficient patients with increased susceptibility to infections, hypogammaglobulinemia, deficient response to vaccination, or low percentages of switched memory B cells. In low- and middle-income countries, the elucidation and study of molecular defects in these patients may take decades.
Objective: To elucidate the genetic defect conferring impaired immunity in a patient diagnosed with common variable immunodeficiency.
PLoS Genet
January 2025
Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement of the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started to shed light on the essential roles of each receptor in different human tissues and cell types. Variants in the ITPR3 gene, which encodes IP3R3, have recently been found to cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J).
View Article and Find Full Text PDFNucleic Acids Res
January 2025
Division of Pharmacoengineering and Molecular Pharmaceutics, The University of North Carolina at Chapel Hill, 125 Mason Farm Rd. Chapel Hill, NC 27599, USA.
Whole genome codon compression-the reassignment of all instances of a specific codon to synonymous codons-can generate organisms capable of tolerating knockout of otherwise essential transfer RNAs (tRNAs). As a result, such knockout strains enable numerous unique applications, such as high-efficiency production of DNA encoding extremely toxic genes or non-canonical proteins. However, achieving stringent control over protein expression in these organisms remains challenging, particularly with proteins where incomplete repression results in deleterious phenotypes.
View Article and Find Full Text PDFAnn Med
December 2025
Department of Basic Medical Sciences, College of Medicine & Center for Genetics and Inherited Diseases, Taibah University Medina, Medina, Saudi Arabia.
Background: Peroxisome biogenesis disorders (PBD) affect multiple organ systems. It is characterized by neurological dysfunction, hypotonia, ocular anomalies, craniofacial abnormalities, and absence of peroxisomes in fibroblasts. PBDs are associated with mutations in any of fourteen different genes, which are involved in peroxisome biogenesis.
View Article and Find Full Text PDFHum Cell
January 2025
Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, 310052, China.
This research delves into Primary Hyperoxaluria Type 2 (PH2), an autosomal recessive disorder precipitated by a unique case of compound heterozygous deleterious mutations in the GRHPR gene, specifically the intron2/3 c.214-2 T > G and the exon8 c.864-865delTG, leading to a premature stop codon at p.
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