{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:43:17Z","timestamp":1775979797738,"version":"3.50.1"},"posted":{"date-parts":[[2025,5,28]]},"group-title":"Neuroscience","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"This research is supported by Division of Intramural Research of NIAID, NIH and intramural research program of"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in\n                  <jats:italic>PIK3R1<\/jats:italic>\n                  , 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\n                  <jats:italic>PIK3R1<\/jats:italic>\n                  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\n                  <jats:italic>PIK3R1<\/jats:italic>\n                  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\n                  <jats:italic>PIK3R1<\/jats:italic>\n                  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\n                  <jats:italic>PIK3R1<\/jats:italic>\n                  haploinsufficiency in neuronal function and survival.\n                <\/jats:p>","DOI":"10.1101\/2025.05.23.655625","type":"posted-content","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T17:40:30Z","timestamp":1748454030000},"source":"Crossref","is-referenced-by-count":0,"title":["A novel frameshift mutation in Phosphoinositide 3-kinase regulatory subunit 1 (\n                  <i>PIK3R1<\/i>\n                  ) causes immunodeficiency and Amyotrophic Lateral Sclerosis (ALS)"],"prefix":"10.64898","author":[{"given":"Brice","family":"Calco","sequence":"first","affiliation":[{"name":"Neuroimmunopathogenesis Unit, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin L.","family":"Sweeney","sequence":"additional","affiliation":[{"name":"Genetic Immunotherapy Section, LCIM, NIAID, NIH, Bethesda, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Steiner","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tongguang","family":"Wang","sequence":"additional","affiliation":[{"name":"Neurodifferentiation Unit, Translational Neuroscience Center, NINDS, NIH, Bethesda, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tovah E.","family":"Markowitz","sequence":"additional","affiliation":[{"name":"Integrated Data Sciences Section, Research Technologies Branch, NIAID, NIH, Bethesda, 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