MMADHC premature termination codons in the pathogenesis of cobalamin D disorder: Potential of translational readthrough reconstitution
| Autor: | Javier de las Heras, Caroline E. Nunes-Xavier, Jesus M. Cortes, Juan Carlos Arango-Lasprilla, Rafael Pulido, Leire Torices |
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| Rok vydání: | 2020 |
| Předmět: |
cblD
endocrine system diseases Translational readthrough Homocystinuria methylmalonic aciduria Biology Cobalamin Stop codon Pathogenesis homocystinuria chemistry.chemical_compound Endocrinology Genetics medicine stop codon Vitamin B12 lcsh:QH301-705.5 Molecular Biology MMADHC lcsh:R5-920 Methylmalonic aciduria Aminoglycoside Premature termination codon premature termination codon medicine.disease Subcellular localization translational readthrough lcsh:Biology (General) chemistry lcsh:Medicine (General) Research Paper |
| Zdroj: | Molecular Genetics and Metabolism Reports Addi. Archivo Digital para la Docencia y la Investigación instname Addi: Archivo Digital para la Docencia y la Investigación Universidad del País Vasco Molecular Genetics and Metabolism Reports, Vol 26, Iss, Pp 100710-(2021) |
| ISSN: | 2214-4269 |
| Popis: | Mutations in the MMADHC gene cause cobalamin D disorder (cblD), an autosomal recessive inborn disease with defects in intracellular cobalamin (cbl, vitamin B12) metabolism. CblD patients present methylmalonic aciduria (MMA), homocystinuria (HC), or combined MMA/HC, and usually suffer developmental delay and cognitive deficits. The most frequent MMADHC genetic alterations associated with disease generate MMADHC truncated proteins, in many cases due to mutations that create premature termination codons (PTC). In this study, we have performed a comprehensive and global characterization of MMADHC protein variants generated by all annotated MMADHC PTC mutations in cblD patients, and analyzed the potential of inducible translational PTC readthrough to reconstitute MMADHC biosynthesis. MMADHC protein truncation caused by disease-associated PTC differentially affected the alternative usage of translation initiation sites, protein abundance, and subcellular localization of MMADHC. Aminoglycoside compounds induced translational PTC readthrough of MMADHC truncated variants, allowing the biosynthesis of full-length MMADHC in a PTC-specific manner. Our results suggest that translational PTC readthrough-based interventions could complement current therapies for cblD patients carrying specific MMADHC PTC mutations. Graphical abstract Unlabelled Image |
| Databáze: | OpenAIRE |
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