The first rule of real estate also applies to genetics. The location of a mutation within a disease gene can affect the physiological defect and the resulting disease symptoms. Dominant spinocerebellar ataxias (SCAs) with different symptoms and severities map to mutations in discrete regions of the same gene, reports a study in the April issue of Nature Genetics.
The hallmark of SCA is loss of motor coordination caused by cerebellar degeneration. The similarity between different types of SCAs stops there. Additional symptoms may include epilepsy, sensory loss, speech difficulties and cognitive decline. The literature describes 26 distinct disease loci for SCA.
Waters et al. mapped the disease locus of a Filipino pedigree with an adult-onset SCA. The roughly 4-cM locus overlapped with SCA locus 13 on chromosome 19, reported for a French family with a more severe SCA. SCA symptoms in the French family began during childhood and included mental retardation and seizures. High-resolution mapping, using known DNA markers, refined the disease locus common to both pedigrees to approximately 800 kb.
Of the 40 genes in the common disease locus, only the voltage-gated potassium channel KCNC3 was expressedin the cerebellum. Sequencing revealed single nucleotide mutations in the same exon of the KCNC3 gene in affected individuals in the Filipino and French pedigrees. A G-to-A mutation at nucleotide 1554 altered an arginine to a histidine (R420H)in the Filipino SCA. A C-to-A mutation at nucleotide 1639 altered a phenylalanine to a leucine (F448L) in the French SCA. The R420H mutation localized to the voltage sensor, whereas the F448L mutation localized to the ion-selective pore of Kv3, the channel encoded by the KCNC3 gene.
Kv3 channels open in a depolarized voltage range and close rapidly. During action potentials, Kv3 channels help the cell to recover quickly in preparation for subsequent action potentials. The authors recorded Kv3 channel activity in Xenopus oocytes expressing wild-type and mutant KCNC3. The R420H mutation resulted in Kv3 channels that did not open at all. Coexpression of R420H mutant protein with wild-type KCNC3 resulted in channels with normal Kv3 gating properties, but reduced current amplitude. F448L channels opened at more hyperpolarized voltages than wild-type channels. F448L channels also stayed open longer, closing seven times more slowly than wild-type channels. The authors suggest that these fundamental changes in gating properties are consistent with the earlier onset and enhanced severity observed in the French SCA.
How would altered Kv3 function result in cerebellar cell death? The authors propose that without a rapid recovery mechanism, sodium and calcium currents might extend and contribute to excitatory cell death. KCNC3 is regulated by reactive oxygen species, so another possibility is that the ability of the cerebellum to withstand oxidative stress might be compromised. Finally, the authors suggest that mutant Kv3 channels may disturb normal cerebellar development. As most known SCA mutations cause polyglutamine expansion in genes with unknown functions, these proposed mechanisms may offer new insight into the etiology of SCA.