{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMTSS2, also known as MTSS1L, is an I‐BAR domain–containing protein that binds to plasma membranes and modulates their curvature. It is highly expressed in the central nervous system and plays an essential role in activity‐dependent synaptic plasticity. In affected individuals, a heterozygous de novo variant in MTSS2 causes global developmental delays, mild intellectual disability, ophthalmological anomalies, and microcephaly, suggesting that appropriate MTSS2 function is crucial for normal neurodevelopment. Studies in Drosophila, in which the ortholog mim is broadly expressed in neurons and some glia, reveal that loss of mim function leads to reduced lifespan, impaired locomotor behavior, and defective synaptic transmission; notably, expression of the human reference MTSS2 rescues these phenotypes, whereas the variant allele demonstrates a partial loss‐of‐function or dominant-negative effect."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nResearch on another I‐BAR domain family member, Abba, further underscores the role of such proteins in regulating membrane dynamics. Abba facilitates growth factor–mediated membrane ruffling and lamellipodia formation by interacting with the GTPase Rac1—a process that is modulated by PDGF stimulation—thereby linking membrane deformation with cytoskeletal rearrangements. This functional parallel emphasizes that proteins harboring I‐BAR domains, like MTSS2, likely utilize similar membrane-bending mechanisms to affect cellular processes, although their roles may diverge depending on the tissue context."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition, insights from studies of the ABBA motif in unrelated proteins illustrate the broader theme that conserved structural elements can mediate critical interactions in diverse cellular contexts. For instance, the ABBA motif found in proteins involved in mitotic regulation binds to the cell cycle regulator CDC20, linking substrate recognition to spindle assembly checkpoint signaling. While this function is distinct from the membrane-modulating activity of I‐BAR proteins, the shared use of the “ABBA” nomenclature highlights how evolutionarily conserved motifs can define unique protein functions across different biological systems."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yan Huang, Gabrielle Lemire, Lauren C Briere, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2022.08.011"}], "href": "https://doi.org/10.1016/j.ajhg.2022.08.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36067766"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36067766"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Datong Zheng, Shuqiong Niu, Dan Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Abba promotes PDGF-mediated membrane ruffling through activation of the small GTPase Rac1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2010.09.087"}], "href": "https://doi.org/10.1016/j.bbrc.2010.09.087"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20875796"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20875796"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Barbara Di Fiore, Norman E Davey, Anja Hagting, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ABBA motif binds APC/C activators and is shared by APC/C substrates and regulators."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Cell (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.devcel.2015.01.003"}], "href": "https://doi.org/10.1016/j.devcel.2015.01.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25669885"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25669885"}]}]}]}