{"doi":"10.1101/2025.05.23.655625","title":"A novel frameshift mutation in Phosphoinositide 3-kinase regulatory subunit 1 ( <i>PIK3R1</i> ) causes immunodeficiency and Amyotrophic Lateral Sclerosis (ALS)","abstract":"Abstract Mutations in PIK3R1 , a regulatory subunit of Class I PI3K, are implicated in immune disorders and neurological conditions. We identified a novel heterozygous pathogenic frameshift mutation (c.1710dup) in PIK3R1 in a patient with common variable immunodeficiency who developed slowly progressive Amyotrophic Lateral Sclerosis. Induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs) demonstrated that this mutation resulted in PIK3R1 haploinsufficiency, with downstream activation of AKT, disruption of neuronal electrical function and increased apoptosis in iPSC-derived motor neurons. Single-cell RNA sequencing (scRNA-seq) and pathway analysis of differentially expressed genes showed apoptosis pathways were upregulated in neuronal clusters from iMNs harboring the PIK3R1 c.1710 dup mutation. Mutated iPSC-derived brain organoids were smaller than matched controls. scRNA-seq of brain organoids showed more active apoptosis in neuronal clusters of patient-derived brain organoids. These findings identify a critical and novel role for PIK3R1 haploinsufficiency in neuronal function and survival.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":566902,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9462,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":417778,"name":"Colin L. Sweeney","orcid":"0000-0002-9442-1134","position":1,"is_corresponding":false},{"id":456109,"name":"Joseph Steiner","orcid":"0000-0003-0284-631X","position":2,"is_corresponding":false},{"id":671213,"name":"Tongguang Wang","orcid":"0000-0003-0195-5661","position":3,"is_corresponding":false},{"id":264931,"name":"Tovah E. Markowitz","orcid":null,"position":4,"is_corresponding":false},{"id":1209467,"name":"Subrata Paul","orcid":"0000-0002-4482-3338","position":5,"is_corresponding":false},{"id":1239168,"name":"Bianca Palicha","orcid":null,"position":6,"is_corresponding":false},{"id":1471146,"name":"Sara Dinges","orcid":null,"position":7,"is_corresponding":false},{"id":1471147,"name":"Kelsey Yoo","orcid":null,"position":8,"is_corresponding":false},{"id":661477,"name":"Lisa Henderson","orcid":"0000-0003-2043-6963","position":9,"is_corresponding":false},{"id":631200,"name":"Valerie McDonald","orcid":null,"position":10,"is_corresponding":false},{"id":238404,"name":"Suk See De Ravin","orcid":"0000-0002-9800-774X","position":11,"is_corresponding":false},{"id":226912,"name":"Benjamin Greenberg","orcid":"0000-0002-2091-8201","position":12,"is_corresponding":false},{"id":332536,"name":"Christa S. Zerbe","orcid":"0000-0003-4219-0503","position":13,"is_corresponding":false},{"id":231247,"name":"Luigi D. Notarangelo","orcid":"0000-0002-8335-0262","position":14,"is_corresponding":false},{"id":104227,"name":"Steven M. Holland","orcid":"0000-0003-3207-5464","position":15,"is_corresponding":false},{"id":230801,"name":"Avindra Nath","orcid":"0000-0003-0927-5855","position":16,"is_corresponding":false},{"id":444928,"name":"Farinaz Safavi","orcid":"0000-0002-8127-2643","position":17,"is_corresponding":false},{"id":1169434,"name":"Brice Calco","orcid":null,"position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:40.491968Z","pmid":"40568112","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":[]}