{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE338nnn/GSE338788/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE338788"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Patient Derived Neomorphic SEPTIN6 Mutations Induce Hematopoietic Stem Cell Senescence Underlying Congenital Neutropenia and Myelodysplasia","description":"Septins are RAS-like GTP-binding proteins involved in cytoskeletal organization and cellular division. We previously described two pediatric patients harboring SEPT6 germline mutations (GM1:SEPT6 c.1282T>C and GM2:SEPT6 c.1282T>A) presenting with congenital neutropenia associated with the development of myelodysplastic syndrome. In one patient, an additional somatic mutation (SM:SEPT6 c.43C>T) was detected at a low allelic fraction in the BM. Here, we describe the consequences of these mutations on hematopoiesis. Transgenic expression or gene editing of GM1 or GM2 in human CD34+ cells led to enlarged, multinucleated cells associated with accelerated exhaustion and premature senescence of hematopoietic stem and progenitor cells (HSPCs). Senescence defects were associated with the upregulation of mTOR phosphorylation; and pharmacologic inhibition of the mTOR pathway resulted in rescue of senescence. In parallel, HSPCs exhibited marked mitochondrial abnormalities, including increased expression of OPA1, a key regulator of mitochondrial fusion, and enhanced oxygen consumption during mitochondrial respiration. Introduction of SM in cis with GM1 mitigated all observed defects. Collectively, our findings demonstrate a gain-of-function mechanism underlying marrow failure in patients carrying germline SEPT6 mutations and suggest that acquisition of a secondary somatic SEPT6 variant may confer a compensatory effect within hematopoietic cells.","dates":{"publication":"2026/07/18"},"accession":"GSE338788","cross_references":{"GSM":["GSM9881448","GSM9881447","GSM9881446","GSM9881445","GSM9881444","GSM9881443","GSM9881442","GSM9881441"],"GPL":["34281"],"GSE":["338788"],"taxon":["Homo sapiens"]}}