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A deficiency of N\u2010glycanase 1, encoded by the <jats:italic>NGLY1<\/jats:italic> gene, results in a congenital disorder of deglycosylation. The NGLY1 enzyme is mainly involved in cleaving N\u2010glycans from misfolded, retro\u2010translocated glycoproteins in the cytosol from the endoplasmic reticulum before their proteasomal degradation or activation. Despite the essential role of NGLY1 in deglycosylation pathways, the exact consequences of NGLY1 deficiency on global cellular protein glycosylation have not yet been investigated. We undertook a multiplexed tandem mass tags\u2010labeling\u2010based quantitative glycoproteomics and proteomics analysis of fibroblasts from <jats:italic>NGLY1<\/jats:italic>\u2010deficient individuals carrying different biallelic pathogenic variants in <jats:italic>NGLY1<\/jats:italic>. This quantitative mass spectrometric analysis detected 8041 proteins and defined a proteomic signature of differential expression across affected individuals and controls. Proteins that showed significant differential expression included phospholipid phosphatase 3, stromal cell\u2010derived factor 1, collagen alpha\u20101 (IV) chain, hyaluronan and proteoglycan link protein 1, and thrombospondin\u20101. We further detected a total of 3255 N\u2010glycopeptides derived from 550 glycosylation sites of 407 glycoproteins by multiplexed N\u2010glycoproteomics. Several extracellular matrix glycoproteins and adhesion molecules showed altered abundance of N\u2010glycopeptides. Overall, we observed distinct alterations in specific glycoproteins, but our data revealed no global accumulation of glycopeptides in the patient\u2010derived fibroblasts, despite the genetic defect in <jats:italic>NGLY1<\/jats:italic>. Our findings highlight new molecular and system\u2010level insights for understanding NGLY1\u2010CDDG.<\/jats:p>","DOI":"10.1002\/jimd.12557","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T07:20:05Z","timestamp":1663140005000},"page":"76-91","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["N\u2010glycoproteomics reveals distinct glycosylation alterations in <scp>NGLY1<\/scp>\u2010deficient patient\u2010derived dermal fibroblasts"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5747-1549","authenticated-orcid":false,"given":"Rohit","family":"Budhraja","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayank","family":"Saraswat","sequence":"additional","affiliation":[{"name":"Department of Laboratory 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