Anchors Aweigh!

Genomics, proteomics, transgenics, molecular medicine: these are some of the scientific catch phrases of the 1990s. The hard work and high expectations of the past decade are beginning to influence reality. Results have accrued to the point that we can begin applying molecular knowledge to therapeutics. Although still in the formative stages, one cannot help but see the vast potential of the exponentially growing molecular knowledge base for understanding physiology and pathophysiology.In recent years, increasing numbers of ion channelopathies—disorders involving mutations in ion channel genes—have been recognized. These disorders include periodic paralyzes, migraine, ataxias, epilepsy, and cardiac arrhythmias to name a few. Research efforts have been directed toward identifying the candidate ion channel genes and their mutations and understanding the functional consequences of these mutations. In many cases, the results have been highly rewarding with a biophysical phenotype that easily correlates with the ultimate clinical phenotype.1 There are also cases where mutations in channel proteins, all of which are known to lead to a clinical disorder, do not have, as yet, a phenotype that is consistent with an interpretable hypothesis. For example, in familial hemiplegic migraine, individual mutations in a Ca2+ channel α subunit gene can apparently cause either loss or gain of function, depending on the mutation.2 3 4 5 6 Perhaps different mutant channels behave differently in their native environment and when interacting with auxiliary proteins. Perhaps additional analysis will reveal a mechanism. Yet at present, it is challenging to reconcile this disparate behavior with the common clinical phenotype of migraine. Presumably, this results from our as-yet limited knowledge …