{"doi":"10.64898/2026.01.20.700518","title":"5′ UTR length regulates alternative N-terminal protein isoform production in health and disease","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>The 5′ untranslated region (5′ UTR) of an mRNA is classically viewed as a regulatory region that controls the amount of protein production, but not the resulting protein sequence. Here, we demonstrate that 5′ UTR length plays a direct role in alternative N-terminal protein isoform production by controlling start codon selection. We find that very short 5′ UTRs enhance leaky ribosome scanning, thereby promoting the production of truncated alternative N-terminal protein isoforms. We also show that endogenous changes in 5′ UTR length due to alternative transcription initiation can tune the relative abundance of alternative N-terminal isoforms from the same gene. In addition, we identify mutations in rare genetic diseases that alter 5′ UTR length, including a deletion in the VHL 5′ UTR in von Hippel–Lindau disease that shifts translation toward the shorter VHLp19 isoform. Together, our results implicate 5′ UTR length as a determinant of alternative N-terminal isoform production and reveal an underappreciated mechanism by which noncoding changes can reshape the proteome.</jats:p>\n                <jats:sec>\n                  <jats:title>Highlights</jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>5′ UTR length affects the landscape of endogenous alternative N-terminal protein isoforms</jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Generation of an alternative truncated AKR7A2 isoform is mediated by short 5′ UTR length</jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Alternative transcription initiation modulates 5′ UTR length to tune N-terminal isoform ratios</jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Pathogenic VHL 5′ UTR variants perturb N-terminal isoform ratios by altering 5′ UTR length</jats:p>\n                    </jats:list-item>\n                  </jats:list>\n                </jats:sec>","journal":null,"year":2026,"id":4320,"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":0.0438,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2026-01-22","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":44671,"name":"Eric M. Smith","orcid":null,"position":1,"is_corresponding":false},{"id":44672,"name":"Matteo Di Bernardo","orcid":null,"position":2,"is_corresponding":false},{"id":44673,"name":"Yi Fei Tao","orcid":"0000-0002-3566-673X","position":3,"is_corresponding":false},{"id":44674,"name":"Elizabeth M. Black","orcid":"0000-0001-9278-1219","position":4,"is_corresponding":false},{"id":44675,"name":"Ekaterina Khalizeva","orcid":"0009-0003-1060-0835","position":5,"is_corresponding":false},{"id":44676,"name":"Iain M. Cheeseman","orcid":"0000-0002-3829-5612","position":6,"is_corresponding":false},{"id":44677,"name":"Erin Smith","orcid":null,"position":7,"is_corresponding":false},{"id":44678,"name":"Elizabeth J. Black","orcid":null,"position":8,"is_corresponding":false},{"id":44670,"name":"Jimmy Ly","orcid":null,"position":0,"is_corresponding":true}],"reference_count":95,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"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":[]}