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We report an individual with severe neurological symptoms including postnatal microcephaly, progressive brain atrophy and global developmental delay associated with a<jats:italic>de novo<\/jats:italic>missense variant (M280L) in the<jats:italic>FOXR1<\/jats:italic>gene. At the protein level, M280L impaired FOXR1 expression and induced a nuclear aggregate phenotype due to protein misfolding and proteolysis. RNAseq and pathway analysis showed that FOXR1 acts as a transcriptional activator and repressor with central roles in heat shock response, chaperone cofactor-dependent protein refolding and cellular response to stress pathways. Indeed, FOXR1 expression is increased in response to cellular stress, a process in which it directly controls<jats:italic>HSPA6<\/jats:italic>,<jats:italic>HSPA1A<\/jats:italic>and<jats:italic>DHRS2<\/jats:italic>transcripts. The M280L mutant compromises FOXR1\u2019s ability to respond to stress, in part due to impaired regulation of downstream target genes that are involved in the stress response pathway. Quantitative PCR of mouse embryo tissues show<jats:italic>Foxr1<\/jats:italic>expression in the embryonic brain. Using CRISPR\/Cas9 gene editing, we found that deletion of mouse<jats:italic>Foxr1<\/jats:italic>leads to a severe survival deficit while surviving newborn<jats:italic>Foxr1<\/jats:italic>knockout mice have reduced body weight. Further examination of newborn<jats:italic>Foxr1<\/jats:italic>knockout brains revealed a decrease in cortical thickness and enlarged ventricles compared to littermate wild-type mice, suggesting that loss of<jats:italic>Foxr1<\/jats:italic>leads to atypical brain development. Combined, these results suggest FOXR1 plays a role in cellular stress response pathways and is necessary for normal brain development.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009854","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T17:23:49Z","timestamp":1635787429000},"page":"e1009854","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["FOXR1 regulates stress response pathways and is necessary for proper brain development"],"prefix":"10.1371","volume":"17","author":[{"given":"Andressa","family":"Mota","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5435-2261","authenticated-orcid":true,"given":"Hannah 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