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TMEM240 has been robustly associated with spinocerebellar ataxia type 21, a neurodegenerative disorder presenting with motor incoordination, cognitive impairment, and neurodevelopmental challenges. Multiple independent studies report autosomal dominant inheritance with clear segregation in affected families. In one case series, three subjects from a single family were found to harbor the recurrent c.196G>A (p.Gly66Arg) variant (PMID:32705938), while additional reports from other groups identified further pathogenic missense changes, including the recurrent c.509C>T (p.Pro170Leu) variant, reinforcing the genetic link.
Beyond isolated case reports, larger multi‐patient cohorts have confirmed the association of TMEM240 variants with a spectrum of clinical presentations ranging from early‐onset cerebellar ataxia to neurodevelopmental delay and even autism spectrum features (PMID:26813285; PMID:33851480). Additional affected relatives in these studies, including cases with maternal and sibling inheritance, further corroborate a clear autosomal dominant pattern, with segregation analyses accounting for at least 19 affected individuals.
Genetic evidence is further strengthened by the recurrence of specific variants. The c.196G>A (p.Gly66Arg) change, directly reported in the neurodevelopmental case series (PMID:32705938), and the c.509C>T (p.Pro170Leu) mutation reported in several studies (PMID:39340213) serve as strong indicators of pathogenicity. These variants are consistently observed across unrelated families, confirming the robust nature of the gene‐disease relationship.
Functional studies provide important mechanistic insight into SCA21 pathogenesis. In vitro experiments demonstrate that mutant TMEM240 leads to impaired clathrin‐mediated endocytosis and autophagic lysosomal degradation, as well as early glial activation in animal models (PMID:30184469). Such experiments, complemented by neuronal culture studies showing disrupted dendritic development, directly parallel clinical observations and support a pathogenic mechanism involving lysosomal dysfunction and subsequent cellular stress.
Integrating both genetic and functional evidence, the association between TMEM240 and spinocerebellar ataxia type 21 is well substantiated. The cumulative data from a variety of case reports, multi‐patient studies with segregation data, and rigorous experimental assays converge to support a strong diagnostic role for TMEM240 genetic testing. Clinicians can therefore consider TMEM240 mutations as definitive markers for SCA21, enabling early intervention and more precise patient management.
Key Take‑home: TMEM240 variants, particularly recurrent missense changes, serve as reliable diagnostic markers for SCA21 due to their robust genetic and functional validation, thereby improving clinical decision‑making and paving the way for targeted therapeutic strategies.
Gene–Disease AssociationStrongMultiple case reports and multi‐patient studies, encompassing over 15 probands across several independent families with autosomal dominant segregation (PMID:32705938; PMID:36123134), in addition to concordant functional data, support the association. Genetic EvidenceStrongRecurrent pathogenic variants, notably c.196G>A (p.Gly66Arg) and c.509C>T (p.Pro170Leu), have been consistently identified in independent cohorts and segregate with the disease phenotype, reinforcing the genetic link. Functional EvidenceModerateFunctional assays in cell and animal models demonstrate disrupted endocytosis, impaired autophagic lysosomal degradation, and early gliosis (PMID:30184469), which mirror critical aspects of the clinical phenotype. |