Reports of primary isolated dystonia inherited in an autosomal-recessive (AR) manner, often lumped together as "DYT2 dystonia," have appeared in the scientific literature for several decades, but no genetic cause has been identified to date. Using a combination of homozygosity mapping and whole-exome sequencing in a consanguineous kindred affected by AR isolated dystonia, we identified homozygous mutations in HPCA, a gene encoding a neuronal calcium sensor protein found almost exclusively in the brain and at particularly high levels in the striatum, as the cause of disease in this family. Subsequently, compound-heterozygous mutations in HPCA were also identified in a second independent kindred affected by AR isolated dystonia. Functional studies suggest that hippocalcin might play a role in regulating voltage-dependent calcium channels. The identification of mutations in HPCA as a cause of AR primary isolated dystonia paves the way for further studies to assess whether "DYT2 dystonia" is a genetically homogeneous condition or not.
Charlesworth, G., Angelova, P. R., Bartolomé-Robledo, F., Ryten, M., Trabzuni, D., Stamelou, M., … Wood, N. W. (2015). Mutations in HPCA cause autosomal-recessive primary isolated dystonia. American Journal of Human Genetics, 96(4), 657–665. https://doi.org/10.1016/j.ajhg.2015.02.007