What Is Known About The Genetics of Pallister-Hall Syndrome?
Molecular biologists have determined that mutations in a gene that is designated GLI3 are causative of PHS. GLI3 encodes a zinc finger protein that is responsible for regulating the production of other proteins, especially at the time of early (i.e., fetal) development. Unfortunately, PHS is an autosomal dominant disorder, which means that only one mutant copy of GLI3 is needed to effect the manifestation of PHS in an individual.
Most PHS-causing mutations affect the GLI3 gene in a manner that causes a shortened version of its protein to be made. This is problematic because whereas normal versions of the GLI3 protein are able to stimulate and repress the activities of certain growth and development genes at critical stages of fetal development, shortened versions of the GLI3 protein are only able to repress these genes. As a result, certain genes that are required for early growth and development are not stimulated, or at least are not adequately stimulated, at critical times in individuals having a GLI3 gene mutation.
Interestingly, not all of the symptoms listed above are generally thought of as "fetal growth and development" symptoms. For example, the development of hypothalamic hamartomas is not a symptom of this variety. Molecular geneticists are currently working to determine why such symptoms are caused by a gene that is highly involved in early growth and development.
Finally, it is also known that some GLI3 mutations, which are namely certain missense mutations, hardly affect the normal activity of GLI3 or its proteins. Those who have a mutation of this kind usually exhibit no or very mild PHS symptoms.