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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Title:	Human ADA2 deficiency is characterized by the absence of an intracellular hypoglycosylated form of adenosine deaminase 2
Creators:	Ehlers, L. ORCID: https://orcid.org/0000-0001-8737-001X, Wouters, M. ORCID: https://orcid.org/0000-0002-4675-1665, Hombrouck, A. ORCID: https://orcid.org/0009-0003-5236-6063, Pillay, B. ORCID: https://orcid.org/0000-0001-7964-544X, Delafontaine, S. ORCID: https://orcid.org/0000-0002-8985-8155, Bucciol, G. ORCID: https://orcid.org/0000-0001-5004-0738, Baggio, M. ORCID: https://orcid.org/0000-0001-6708-9925, Dzhus, M. ORCID: https://orcid.org/0000-0002-2077-4295, Francés Rabanal, E., Damerau, A. ORCID: https://orcid.org/0000-0001-6651-2963, Neugebauer, J. ORCID: https://orcid.org/0000-0002-2576-1012, Ebstein, F. ORCID: https://orcid.org/0000-0002-3729-7878, Jacquemyn, M. ORCID: https://orcid.org/0000-0003-2626-4189, De Somer, L. ORCID: https://orcid.org/0000-0002-8488-5090, Schrijvers, R. ORCID: https://orcid.org/0000-0002-4261-6220, Vanderschueren, S. ORCID: https://orcid.org/0000-0002-4003-5465, Cassiman, D. ORCID: https://orcid.org/0000-0002-6154-0970, Kirchner, M. ORCID: https://orcid.org/0000-0002-7049-534X, Mertins, P. ORCID: https://orcid.org/0000-0002-2245-528X, Mashreghi, M.F., Kallinich, T. ORCID: https://orcid.org/0000-0003-2404-9397, Daelemans, D. ORCID: https://orcid.org/0000-0001-7092-1153, Agostinis, P. ORCID: https://orcid.org/0000-0003-1314-2115, Moens, L. ORCID: https://orcid.org/0000-0002-5347-6526 and Meyts, I. ORCID: https://orcid.org/0000-0003-1214-0302
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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