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Despite its relevance, many aspects of TTBK2 function in both physiological and pathological conditions remain poorly understood. Truncating variants in\n                    <jats:italic>TTBK2<\/jats:italic>\n                    gene cause\n                    <jats:bold>s<\/jats:bold>\n                    pinocerebellar ataxia type 11 (SCA11), a rare form of autosomal dominant cerebellar ataxia. However, the functional consequences and pathogenic potential of missense variants have yet to be elucidated. In this study, we developed a CRISPR\/Cas9 knock-in cell model harboring a missense variant in TTBK2 kinase domain (NM_173500.4:c.625\u00a0C\u2009&gt;\u2009T; p.Leu209Phe) to evaluate its impact on TTBK2 expression, associated protein levels, and phosphoproteomic profiles.\n                    <jats:italic>TTBK2<\/jats:italic>\n                    missense variant (TTBK2-L209F) was associated with reduced TTBK2 protein levels, altered levels of cytoskeleton-related proteins, and impaired kinase activity, namely toward TDP-43. Phosphoproteomic analyses identified dysregulation in pathways linked to gene regulation, protein degradation, cytoskeletal organization, and TGF-\u03b2 signaling. These findings provide valuable insights into the biological roles of TTBK2 in cellular signaling. Moreover, this study underscores the importance of functional studies to better understand the consequences of\n                    <jats:italic>TTBK2<\/jats:italic>\n                    missense variants, particularly those affecting the kinase domain, and their potential contribution to disease.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-32288-0","type":"journal-article","created":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T02:36:49Z","timestamp":1766284609000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Missense variant in TTBK2 kinase domain causes loss of function and impaired protein phosphorylation"],"prefix":"10.1038","volume":"16","author":[{"given":"Daniela","family":"Fel\u00edcio","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hugo","family":"Os\u00f3rio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Concei\u00e7\u00e3o","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Filipa","family":"Brand\u00e3o","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jo\u00e3o Parente","family":"Freixo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00eas","family":"Carvalho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Paula","family":"Sousa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margarida","family":"Castro-Caldas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Sequeiros","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Lemos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,21]]},"reference":[{"key":"32288_CR1","doi-asserted-by":"crossref","unstructured":"Ikezu, S. & Ikezu, T. 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