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Int. J. Mol. Sci. 2017, 18(4), 706; doi:10.3390/ijms18040706

Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production

1
Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany
2
Gene Therapy Center and Department of Ophthalmology, University of North Carolina, Chapel Hill, NC 27302, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Cheorl-Ho Kim
Received: 16 December 2016 / Revised: 17 March 2017 / Accepted: 22 March 2017 / Published: 26 March 2017
View Full-Text   |   Download PDF [1556 KB, uploaded 27 March 2017]   |  

Abstract

Aspartylglucosaminidase (AGA) is a lysosomal hydrolase that participates in the breakdown of glycoproteins. Defects in the AGA gene result in a lysosomal storage disorder, aspartylglucosaminuria (AGU), that manifests mainly as progressive mental retardation. A number of AGU missense mutations have been identified that result in reduced AGA activity. Human variants that contain either Ser or Thr in position 149 have been described, but it is unknown if this affects AGA processing or activity. Here, we have directly compared the Ser149/Thr149 variants of AGA and show that they do not differ in terms of relative specific activity or processing. Therefore, Thr149 AGA, which is the rare variant, can be considered as a neutral or benign variant. Furthermore, we have here produced codon-optimized versions of these two variants and show that they are expressed at significantly higher levels than AGA with the natural codon-usage. Since optimal AGA expression is of vital importance for both gene therapy and enzyme replacement, our data suggest that use of codon-optimized AGA may be beneficial for these therapy options. View Full-Text
Keywords: aspartylglucosaminidase; lysosomal storage disorder; aspartylglucosaminuria; lysosomes; single nucleotide polymorphism; gene therapy aspartylglucosaminidase; lysosomal storage disorder; aspartylglucosaminuria; lysosomes; single nucleotide polymorphism; gene therapy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Banning, A.; König, J.F.; Gray, S.J.; Tikkanen, R. Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production. Int. J. Mol. Sci. 2017, 18, 706.

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