{"doi":"10.1210/endocr/bqab246","title":"Novel Pathogenic De Novo <i>INS</i> p.T97P Variant Presenting With Severe Neonatal DKA","abstract":"Pathogenic INS gene mutations are causative for mutant INS-gene-induced diabetes of youth (MIDY). We characterize a novel de novo heterozygous INS gene mutation (c.289A>C, p.T97P) that presented in an autoantibody-negative 5-month-old male infant with severe diabetic ketoacidosis. In silico pathogenicity prediction tools provided contradictory interpretations, while structural modeling indicated a deleterious effect on proinsulin folding. Transfection of wildtype and INS p.T97P expression and luciferase reporter constructs demonstrated elevated intracellular mutant proinsulin levels and dramatically impaired proinsulin/insulin and luciferase secretion. Notably, proteasome inhibition partially and selectively rescued INS p.T97P-derived luciferase secretion. Additionally, expression of INS p.T97P caused increased intracellular proinsulin aggregate formation and XBP-1s protein levels, consistent with induction of endoplasmic reticulum stress. We conclude that INS p.T97P is a newly identified pathogenic A-chain variant that is causative for MIDY via disruption of proinsulin folding and processing with induction of the endoplasmic reticulum stress response.","journal":"Endocrinology","year":2021,"id":211440,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"is_data_producer":false,"deposit_databanks":null,"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":800932,"name":"Hannah Moeller","orcid":"0000-0002-3733-5459","position":1,"is_corresponding":false},{"id":345086,"name":"Ella A. Thomson","orcid":"0000-0002-3294-3092","position":2,"is_corresponding":false},{"id":516309,"name":"Timothy M. Horton","orcid":"0000-0003-2041-3614","position":3,"is_corresponding":false},{"id":800933,"name":"Sooyeon Lee","orcid":"0000-0002-1076-3314","position":4,"is_corresponding":false},{"id":801335,"name":"Raquel Freeman","orcid":null,"position":5,"is_corresponding":false},{"id":645921,"name":"Priya Prahalad","orcid":"0000-0002-3894-4344","position":6,"is_corresponding":false},{"id":345088,"name":"Ada S. Y. Poon","orcid":"0000-0003-2647-6069","position":7,"is_corresponding":false},{"id":516314,"name":"Justin P. Annes","orcid":"0000-0001-8431-3589","position":8,"is_corresponding":false},{"id":800931,"name":"Rayhan Lal","orcid":"0000-0002-8055-944X","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-18T23:52:20.112538Z","pmid":"34888628","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":[]}