Twenty-nine known mutations in this gene are associated with FHM2 (table 2), many clustering in the large intracellular loop between membrane-spanning segments 4 and 5 (figure 1). Twelve of these mutations have been studied by expression in model cells. All but one have shown either complete loss of function or more complex decreases in ATPase activity or potassium sensitivity. Astrocytes expressing these mutant ion pumps will have much higher resting potentials and are believed to lead to disease through a poorly understood mechanism. FHM3 (SCN1A)
The final known locus FHM3 is the SCN1A gene, which encodes a sodium channel α subunit. The only study so far that has found mutations in this gene discovered the same Q1489K mutation in three of 20 families (15%) with 11 other kindreds (55%) already having mutations in CACNA1A or ATP1A2. This mutation is located in a highly conserved region of an intracellular loop connecting domains three and four. This mutation results in a greatly hastened (two- to four-fold) recovery from inactivation compared to wild-type. As this channel is important for action potential generation in neurons,  the Q1489K mutant is expected to result in hyperexcitable neurons. FHM4 (1q31)
The final locus for FHM maps to the q-arm of chromosome 1. A number of attractive candidate genes occur in this area, though no mutations in them have yet been linked to FHM4.
Pathophysiology
FHM1 (CACNA1A)
The first discovered FHM locus was the CACNA1A gene (originally named CACNL1A4), which encodes the P/Q-type calcium channel CaV2.1. Currently, 17  mutations in this channel are known (table 1), and these mutations are distributed throughout the channel. Some of these mutations result in patients with notable cerebellar degeneration or other dysfunction, including one mutation (S218L), which may be related to severe responses to mild concussion, up to and including delayed cerebral edema, coma, and death. Fifteen of these mutants have received at least some further analysis at the electrophysiological level to attempt to determine how they might lead to the FHM1 phenotype. Contradiction in the literature is increasing as to the end result of these mutations on channel kinetics and neuronal excitability.A good example of this contradiction can be seen in the literature regarding the R192Q mutation. The first investigation of this mutation, using the rabbit isoform of the channel expressed in oocytes, found that it did not alter any measured channel properties. A subsequent report, using human channels expressed in HEK293 cells, found a small, hyperpolarizing shift in the midpoint for activation, a result common among FHM1 mutants. This shift results in channels that open at more negative potentials, thus have a higher open probability than wild-type channels at most potentials. This report also found that the R192Q mutant produced almost twice as much whole-cell current compared to wild-type channels. This is not due to a change in single channel conductance, but to an equivalent increase in channel density.