Unravelling the cause of dystonia

Some weeks ago, we got a mail from the Journal of Neurology that our paper "Genome sequencing identifies a novel mutation in ATP1A3 in a New Zealand family with dystonia in females only" got accepted for publication. Today, this paper is also found online. This is joint work between the institute of neurogenetics, in particular Katja, and the IIEG.

To sum up the paper, we identified a likely causal variant in a family with rapid onset dystonia-parkinsonism (RDP). The variant in the ATP1A3 gene is an in-frame deletion of a single amino acid and lies in an important functional domain of the protein. The phenotype in our family was initially not recognised as RDP. Having found the variant in the ATP1A3 gene, the phenotype was carefully re-examined and RDP diagnosed. Such phenotype re-evaluation based on genetic findings is often referred to as 'reverse phenotyping' and demonstrates the use of next generation sequencing in diagnosis of rare disorders.

Variants in ATP1A3 are known to express varying levels of disease expression, also known as reduced penetrance. In our family, one of seven mutation carriers show reduced penetrance, which is in the expected range of 30%. Initially, we expected an X-linked transmission of disease in our investigated family. However, the family has almost only female offspring and hence this could just be by chance. Supporting the initial hypothesis, all affected mutation carriers are females and the unaffected mutation carrier a male. This could imply that the reduced penetrance is due to an unknown modifying factor. However, with only one patient, we cannot elucidate this with sufficient evidence.

ATP1A3 is linked to several neurological disorders such as alternating hemiplegia of childhood (AHC), and CAPOS syndrome. It has been reported earlier that RDP and AHC patients have several shared phenotypic features. These include abrupt onset after specific trigger and a rostrocaudal gradient of involvement with prominent bulbar findings. Hence, RDP and AHC may represent prototype disorders in a larger phenotypic spectrum. Additional reports on variants in the ATP1A3 gene may further elucidate the clinical spectrum and provide a more detailed knowledge on the overlapping phenotypic features.

..this is just a short summary of the work, a more detailed description can be found here.

I always love to work together with the colleagues at the institute of neurogenetics. It is impressing to work with such fantastic scientists and I learn a lot from it. I look forward to our upcoming projects and especially to our recently accepted university grant on "molecular mechanisms of disease expression modifiers".



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