Human ADA2 deficiency is characterized by the absence of an intracellular hypoglycosylated form of adenosine deaminase 2

Ehlers, L.; Wouters, M.; Hombrouck, A.; Pillay, B.; Delafontaine, S.; Bucciol, G.; Baggio, M.; Dzhus, M.; Francés Rabanal, E.; Damerau, A.; Neugebauer, J.; Ebstein, F.; Jacquemyn, M.; De Somer, L.; Schrijvers, R.; Vanderschueren, S.; Cassiman, D.; Kirchner, M.; Mertins, P.; Mashreghi, M.F.; Kallinich, T.; Daelemans, D.; Agostinis, P.; Moens, L.; Meyts, I.

Human ADA2 deficiency is characterized by the absence of an intracellular hypoglycosylated form of adenosine deaminase 2

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Item Type:	Preprint
Title:	Human ADA2 deficiency is characterized by the absence of an intracellular hypoglycosylated form of adenosine deaminase 2
Creators Name:	Ehlers, L., Wouters, M., Hombrouck, A., Pillay, B., Delafontaine, S., Bucciol, G., Baggio, M., Dzhus, M., Francés Rabanal, E., Damerau, A., Neugebauer, J., Ebstein, F., Jacquemyn, M., De Somer, L., Schrijvers, R., Vanderschueren, S., Cassiman, D., Kirchner, M., Mertins, P., Mashreghi, M.F., Kallinich, T., Daelemans, D., Agostinis, P., Moens, L. and Meyts, I.
Abstract:	Human deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by pathogenic variants in ADA2 that lead to impaired deaminase activity. Recently, a lysosomal function of ADA2 has been proposed but an intracellular form of the protein has not yet been characterized. Here, we analyze protein expression of mutant ADA2 in human monocyte-derived macrophages from 10 DADA2 patients. We identify an intracellular low-molecular-weight (LMW) form of ADA2 that undergoes glycan trimming by α-mannosidases and is absent in DADA2 macrophages. Subcellular fractionation and immunofluorescence microscopy demonstrate that LMW-ADA2 is localized in the lysosomes. By overexpression of 34 ADA2 variants in HEK293T and U-937 cells, we show that absence of LMW-ADA2 strongly correlates with reduced deaminase activity and predicts variant pathogenicity. In conclusion, we describe a previously unreported intracellular hypoglycosylated form of ADA2 and establish the absence of this LMW-ADA2 as a cellular characteristic of DADA2. Thereby, we introduce a protein correlate of the recently described lysosomal form of ADA2.
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2023.10.25.564037
Date:	16 February 2026
Official Publication:	https://doi.org/10.1101/2023.10.25.564037

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