Preliminary Considerations

Nature of Genetic Defect
The nature of the human genetic defect informs the approach to modeling the disorder.
If the defect is caused by a recessive loss of function mutation or a dominant
hapoloinsufficiency, then the modeling of the disorder will require inactivating or
attenuating the function of the gene in question. If the defect is caused by a dominant
gain of function mutation, then a transgenic approach may provide a suitable model.
Subsumed in the gain of function mechanism are dominant activating mutations, which
enhance the function of the gene product, as well as dominant negative mutations,
which inactivate the protein in question and also abrogate the activity of the wild-type
protein. Both mechanisms can be modeled by transgenic approaches. In the case of the
dominant activating mutation, it may not be necessary to express the mutant form of
the protein; simple overexpression of the wild-type gene may be sufficient to produce
a phenotype. In the case of a dominant negative mechanism, expression of the mutant
protein would be necessary to produce the phenotype.