{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nEarly genetic studies in autosomal dominant cerebellar ataxias revealed considerable heterogeneity, with linkage analyses in French families mapping novel ataxia loci. These investigations laid the groundwork for identifying new genetic causes of cerebellar degeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBuilding on these mapping studies, whole‐exome sequencing in affected families pinpointed heterozygous mutations in TMEM240 as the causative alteration in spinocerebellar ataxia type 21 (SCA21). A spectrum of missense and truncating mutations in this highly conserved transmembrane protein was associated with early-onset cerebellar ataxia, variable cognitive impairment, and both hypokinetic and hyperkinetic movement disorders, highlighting the broad clinical variability of the disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nInvestigations into TMEM240’s normal biology have demonstrated that it is robustly expressed in neurons across multiple brain regions. Immunofluorescence studies in mouse brain indicate high expression levels in the hippocampus, isocortex, and especially the cerebellum, where TMEM240 localizes predominantly to the post‐synaptic domains of Purkinje cells and is thus likely critical for organizing synaptic inputs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in neuronal network architecture, alterations in the methylation state of the TMEM240 promoter have been implicated in oncogenesis. Aberrant DNA methylation affecting TMEM240 expression is emerging as a potential noninvasive biomarker for early detection, prognosis, and recurrence prediction in colorectal cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the cellular level, TMEM240 has been shown to form distinct multilayered structures—referred to as TMEM240‐Bodies—in neurons. These structures depend on the integrity of TMEM240’s two transmembrane domains and appear to involve interactions with proteins such as Emerin, with peroxisomes contributing to their formation. This unique subcellular assembly suggests specific roles in intracellular organization and signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nComplementing its neural and cellular functions, further studies have expanded the spectrum of TMEM240 involvement to oncological settings, with alterations also noted in breast cancer where they may serve to monitor treatment response and disease progression. Moreover, detailed clinical evaluations of SCA21 have emphasized that TMEM240 mutations can yield a multisystem disorder characterized not only by cerebellar ataxia and cognitive deficits but also by a complex array of movement disorders—including both hyperkinetic and hypokinetic features—underscoring the protein’s multifaceted role in human pathology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Isabelle Vuillaume, David Devos, Susanna Schraen-Maschke, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awu202"}], "href": "https://doi.org/10.1093/brain/awu202"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25070513"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25070513"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Andreas Traschütz, Judith van Gaalen, Mayke Oosterloo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The movement disorder spectrum of SCA21 (ATX-TMEM240): 3 novel families and systematic review of the literature."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Parkinsonism Relat Disord (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.parkreldis.2018.11.027"}], "href": "https://doi.org/10.1016/j.parkreldis.2018.11.027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30522958"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30522958"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Mégane Homa, Anne Loyens, Sabiha Eddarkaoui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The TMEM240 Protein, Mutated in SCA21, Is Expressed in Purkinje Cells and Synaptic Terminals."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cerebellum (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12311-020-01112-y"}], "href": "https://doi.org/10.1007/s12311-020-01112-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32002801"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32002801"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Shih-Ching Chang, Phui-Ly Liew, Muhamad Ansar, et al. 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