Repolarization matters: mutations in the Kv4.3 potassium channel cause SCA19/22.

I n this issue of Annals of Neurology, Duarri et al 1 and Lee et al 2 report the identification of a gene that when mutated causes a new form of spinocerebellar ataxia (SCA). SCAs comprise a group of neurodegenerative diseases that primarily affect cerebellar neurons, but can also involve other neuronal groups such as the extrapyramidal systems, brainstem, and motor neurons. By convention and in contradistinction to Parkinson disease (PARK) and dystonia (DYT) genes, the gene symbol SCA is reserved for autosomal-dominant forms of ataxia. A great number of SCA genes have been identified, with the polyglut-amine ataxia genes representing the largest group. Worldwide , SCA3 and SCA6 are the most common SCA genes, followed by SCA2 and SCA1 (reviewed in Whaley et al 3 and Tsuji et al 4). In prior studies, both groups had independently mapped a new ataxia locus to partially overlapping segments of human chromosome 1. This explains the confusing designations of SCA19 5 and SCA22 6 for what in the end turned out to be mutations in the same gene. Using the 2 original large families and several subsequent smaller families, the 2 groups identified mutations in KCND3. KCND3 encodes Kv4.3, a Shal-related voltage-gated potassium channel involved in the transient outward A-type K þ current in neurons and cardiac myocytes. 7 The 2 groups employed very similar strategies to identify the novel gene, making use of exome capture and next-generation sequencing technology. Whole exome sequencing is now increasingly used for gene identification and was recently successfully utilized to identify a new dominant ataxia in a single Chinese family. 8 Both groups queried variation in expressed parts of the ge-nome including a (near) totality of all protein-coding regions in patients and unaffected individuals. The resulting tens of thousands of variants were filtered by their absence in the ever-growing repositories of normal sequence variants and their location in the candidate region on chromosome 1. When these variants, numbering in the teens after the first filtering step, were further filtered by their likely effect on protein function and cosegregation with the disease in large families, only a single variant per respective family remained. The mutations identified by whole exome sequenc-ing and by subsequent targeted resequencing in unknown ataxia cases are summarized in the Table. This table also lists commonly used criteria that serve to differentiate benign variants from disease-causing mutations. These encompass genetic criteria (cosegregation of the …