Migraine genes and the relation to gender.

Migraine is an episodic brain disorder that is characterized by recurrent attacks of severe unilateral headache that are accompanied by various neurological symptoms. In addition, many patients have what is called an aura with visual and sensory disturbances. The majority of patients are female, suggesting that female hormones play an important role in the pathophysiology of the disorder. The molecular mechanisms, however, underlying this female preponderance are not well understood. It can be expected that the field of genetics that aims at identifying genetic factors that cause migraine by lowering the threshold for attacks will unravel some of these mechanisms. The 3 best known migraine genes encode ion transporters and were identified in families with familial hemiplegic migraine (FHM), a rare subtype of migraine with aura. FHM gene mutations cause alterations in mechanisms that control and modulate the neurotransmitter balance in the brain. Transgenic mice knock-in with human pathogenic mutations that were shown to exhibit some migraine-relevant features were very helpful in dissecting molecular mechanisms of migraine and pointed to a central role for cortical glutamate. In addition, transgenic mice that overexpress human RAMP1 exist and exhibit an increased sensitivity to calcitonin gene-related peptide. Findings from genetic and animal experiments on gender differences in migraine are discussed. Recently, a role for glutamate also came forward from a genome-wide association study in common migraine. By deciphering genetic and pathogenic migraine pathways, it can be expected that in the near future we will better understand mechanisms behind the female preponderance in migraine.