Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
This summary describes the association between TOR1AIP2 and dystonic disorder (MONDO_0003441). In two independent families, a rare TOR1AIP2 variant, c.1234>G (p.Arg412Gly) (PMID:40088780), was identified in patients presenting with a complex movement phenotype characterized by dystonia and hemichorea/hemiballism. The variant is absent from more than 1000 dystonia cases, and although detailed segregation data on additional affected relatives is limited, its discovery in separate families supports a potential autosomal dominant inheritance model. Genetic assessment is constrained by the small number of probands; however, the variant’s rarity and its consistency with the disease presentation provide a preliminary association. The evidence, while promising, is currently limited in scope and awaits further replication and deeper segregation analyses. Overall, the genetic findings lay the groundwork for further investigation into TOR1AIP2 as a candidate gene for this dystonic disorder.
Functional studies offer additional insight into the pathogenic mechanism. A co‑purification assay revealed that the p.Arg412Gly variant disrupts the binding between LULL1 and TorsinA, mimicking the impairment seen in established DYT1 dystonia (PMID:40088780). This reduced protein interaction suggests a mechanism involving compromised nuclear envelope architecture and potentially haploinsufficiency or a dominant‑negative effect. When integrated with the limited genetic evidence, these experimental findings bolster the biological plausibility for TOR1AIP2’s role in dystonic disorder. These results are not only clinically relevant but may also inform diagnostic decision‑making and commercial genetic testing panels. Key take‑home: early identification of candidate variants, combined with functional validation, enhances clinical utility even in disorders with complex genetic underpinnings.
Gene–Disease AssociationLimitedAssociation based on two unrelated families harboring a rare c.1234>G (p.Arg412Gly) variant with a dystonic disorder phenotype; limited segregation data available (PMID:40088780). Genetic EvidenceLimitedEvidence from two probands with the same variant that is absent in >1000 control dystonia cases supports a candidate association, though broader replication and additional segregation studies are needed (PMID:40088780). Functional EvidenceModerateFunctional assays demonstrate reduced binding between mutant LULL1 and TorsinA, consistent with disrupted nuclear envelope function, reinforcing the pathogenic potential of the variant (PMID:40088780). |