Recent advances in studies of the molecular basis of endocrine disease

The molecular basis for a number of endocrine disorders has been determined in the last several years. Mutations have been described at multiple different steps in the pathways of hormone action. There are now examples of mutations in hormones themselves, hormone receptors, second messenger signalling pathways, and the transcription factors that transduce hormone signals. Several common themes emerge even from the relatively small number of mutations that have been described to date. First, the phenotypic variability that characterizes many endocrine diseases is also reflected in genetic heterogeneity. Some clinical phenotypes that were thought previously to represent distinct diseases can now be interpreted as manifestations of different types of mutations within a single gene. Second, the propensity of certain genes to be targets for frequent mutations may be explained in part by gene structure and organization. Third, although many of the mutations reported initially have been associated with severely affected patients, it is likely that mutations with less severe consequences will also be identified. Genetic polymorphisms within the normal population could also cause subtle differences in hormone or receptor activity, thereby constituting part of the basis for variability in hormone levels and activity. Finally, one can predict continued rapid advances in this field with transfer of genetic testing into clinical practice in the near future.