{"doi":"10.2337/dc20-2317","title":"Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation","abstract":"OBJECTIVE Multiple genome-wide association studies have identified a strong genetic linkage between the SKAP2 locus and type 1 diabetes (T1D), but how this leads to disease remains obscure. Here, we characterized the functional consequence of a novel SKAP2 coding mutation in a patient with T1D to gain further insight into how this impacts immune tolerance. RESEARCH DESIGN AND METHODS We identified a 24-year-old individual with T1D and other autoimmune and inflammatory conditions. The proband and first-degree relatives were recruited for whole-exome sequencing. Functional studies of the protein variant were performed using a cell line and primary myeloid immune cells collected from family members. RESULTS Sequencing identified a de novo SKAP2 variant (c.457G>A, p.Gly153Arg) in the proband. Assays using monocyte-derived macrophages from the individual revealed enhanced activity of integrin pathways and a migratory phenotype in the absence of chemokine stimulation, consistent with SKAP2 p.Gly153Arg being constitutively active. The p.Gly153Arg variant, located in the well-conserved lipid-binding loop, induced similar phenotypes when expressed in a human macrophage cell line. SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, likely resulting in a break in immune tolerance and T1D. CONCLUSIONS SKAP2 plays a key role in myeloid cell activation and migration. This particular mutation in a patient with T1D and multiple autoimmune conditions implicates a role for activating SKAP2 variants in autoimmune T1D.","journal":"Diabetes Care","year":2021,"id":189237,"datarank":0.842590938798718,"base_score":2.772588722239781,"endowment":2.772588722239781,"self_citation_contribution":0.41588830833596724,"citation_network_contribution":0.42670263046275086,"self_endowment_contribution":0.41588830833596724,"citer_contribution":0.42670263046275086,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":13,"citers_with_citation_signal":10,"citers_with_endowment":10,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8976,"is_data_producer":true,"deposit_databanks":{"figshare":["10.2337/figshare.14192315"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":751837,"name":"Chester E. Chamberlain","orcid":null,"position":1,"is_corresponding":false},{"id":751342,"name":"Wesley Dixon","orcid":"0000-0002-5080-1522","position":2,"is_corresponding":false},{"id":751838,"name":"Lauren Spector","orcid":null,"position":3,"is_corresponding":false},{"id":499606,"name":"Lisa R. Letourneau","orcid":"0000-0001-9465-4870","position":4,"is_corresponding":false},{"id":626194,"name":"Wint Lwin","orcid":"0000-0003-0964-2627","position":5,"is_corresponding":false},{"id":230363,"name":"Louis H. Philipson","orcid":"0000-0002-2208-3607","position":6,"is_corresponding":false},{"id":108935,"name":"Alexander Zarbock","orcid":"0000-0002-2124-1714","position":7,"is_corresponding":false},{"id":751839,"name":"Karline Saintus","orcid":null,"position":8,"is_corresponding":false},{"id":136471,"name":"Juehu Wang","orcid":null,"position":9,"is_corresponding":false},{"id":308644,"name":"Michael S. German","orcid":"0000-0003-3833-7680","position":10,"is_corresponding":false},{"id":235418,"name":"Mark S. Anderson","orcid":"0000-0002-3093-4758","position":11,"is_corresponding":false},{"id":322389,"name":"Clifford A. Lowell","orcid":"0000-0002-0467-7073","position":12,"is_corresponding":false},{"id":751341,"name":"Niklas Rutsch","orcid":"0000-0001-5035-2264","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-18T23:49:14.547082Z","pmid":"34172489","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}