A novel frameshift mutation in Phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1) causes immunodeficiency and Amyotrophic Lateral Sclerosis (ALS).

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 PIK3R1c.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.