Journal article

Publication year: 2018

Pages: 668-675

Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Volume number: 1864

Issue number: 3

ISSN: 0925-4439

eISSN: 0006-3002

Open access status: Bronze

DOI Link: https://doi.org/10.1016/j.bbadis.2017.12.014

Publisher: Elsevier

Abstract: 
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by mutations in the gene for aspartyl-glucosaminidase (AGA). This enzyme participates in glycoprotein degradation in lysosomes. AGU results in progressive mental retardation, and no curative therapy is currently available. We have here characterized the consequences of AGA gene mutations in a compound heterozygous patient who exhibits a missense mutation producing a Ser72Pro substitution in one allele, and a nonsense mutation Trp168X in the other. Ser72 is not a catalytic residue, but is required for the stabilization of the active site conformation. Thus, Ser72Pro exchange impairs the autocatalytic activation of the AGA precursor, and results in a considerable reduction of the enzyme activity and in altered AGA precursor processing. Betaine, which can partially rescue the AGA activity in AGU patients carrying certain missense mutations, turned out to be ineffective in the case of Ser72Pro substitution. The Trp168X nonsense allele results in complete lack of AGA polypeptide due to nonsense-mediated decay (NMD) of the mRNA. Amlexanox, which inhibits NMD and causes a translational read-through, facilitated the synthesis of a full-length, functional AGA protein from the nonsense allele. This could be demonstrated as presence of the AGA polypeptide and increased enzyme activity upon Amlexanox treatment. Furthermore, in the Ser72Pro/Trp168X expressing cells, Amlexanox induced a synergistic increase in AGA activity and polypeptide processing due to enhanced processing of the Ser72Pro polypeptide. Our data show for the first time that Amlexanox might provide a valid therapy for AGU.

Harvard Citation style: Banning, A., Schiff, M. and Tikkanen, R. (2018) Amlexanox provides a potential therapy for nonsense mutations in the lysosomal storage disorder Aspartylglucosaminuria, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1864(3), pp. 668-675. https://doi.org/10.1016/j.bbadis.2017.12.014

APA Citation style: Banning, A., Schiff, M., & Tikkanen, R. (2018). Amlexanox provides a potential therapy for nonsense mutations in the lysosomal storage disorder Aspartylglucosaminuria. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1864(3), 668-675. https://doi.org/10.1016/j.bbadis.2017.12.014