{"doi":"10.3389/fnmol.2022.994513","title":"A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology","abstract":"The Rac1 guanine exchange factor Kalirin-7 is a key regulator of dendritic spine morphology, LTP and dendritic arborization. Kalirin-7 dysfunction and genetic variation has been extensively linked to various neurodevelopmental and neurodegenerative disorders. Here we characterize a Kalirin-7 missense mutation, glu1577lys (E1577K), identified in a patient with severe developmental delay. The E1577K point mutation is located within the catalytic domain of Kalirin-7, and results in a robust reduction in Kalirin-7 Rac1 Guanosine exchange factor activity. In contrast to wild type Kalirin-7, the E1577K mutant failed to drive dendritic arborization, spine density, NMDAr targeting to, and activity within, spines. Together these results indicate that reduced Rac1-GEF activity as result of E1577K mutation impairs neuroarchitecture, connectivity and NMDAr activity, and is a likely contributor to impaired neurodevelopment in a patient with developmental delay.","journal":"Frontiers in Molecular Neuroscience","year":2022,"id":285802,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":457133,"name":"Roos Anouk Voorn","orcid":"0000-0002-0007-9359","position":1,"is_corresponding":false},{"id":460997,"name":"María Dolores Martin‐de‐Saavedra","orcid":"0000-0001-8527-493X","position":2,"is_corresponding":false},{"id":458092,"name":"Daniel Loizzo","orcid":null,"position":3,"is_corresponding":false},{"id":669382,"name":"Marc Dos Santos","orcid":"0000-0002-6101-5631","position":4,"is_corresponding":false},{"id":301377,"name":"Peter Penzes","orcid":"0000-0001-5449-1640","position":5,"is_corresponding":false},{"id":372410,"name":"Euan Parnell","orcid":"0000-0002-2590-2786","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T00:29:44.944555Z","pmid":"36533124","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":[]}