Charlesworth, G;
Angelova, PR;
Bartolomé-Robledo, F;
Ryten, M;
Trabzuni, D;
Stamelou, M;
Abramov, AY;
... Wood, NW; + view all
(2015)
Mutations in HPCA cause autosomal-recessive primary isolated dystonia.
American Journal of Human Genetics
, 96
(4)
pp. 657-665.
10.1016/j.ajhg.2015.02.007.
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Abstract
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.
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