Syndromes Caused by the Mutations in GLI3 Gene

Responsible gene for Greig cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome (PHS), Postaxial polydactyly type-A (PAP-A), and Preaxial polydactyly type-IV (PPD-IV) has been known to be GLI3. In the present review, relationship between mutation points of GLI3 and resulting phenotypes is discussed. It has been proposed that mutations in the upstream or within zinc finger domain of GLI3 gene induce GCPS, those in the post zinc finger region including protease cleavage site induce PHS, and those in far 3' terminal of GLI3 gene induce PAP-A and PPD-IV. Meanwhile, it has been known that mutations in the near 3' terminal end also induce GCPS. There is an argument whether clear genotype-phenotype correlations were apparent or not. A lot of mutant and knockout mice in Gli3 gene, which exhibit similar phenotypes to human syndromes caused by GLI3 mutations, have been maintained and produced. Investigations using mouse homolog of GCPS, PHS and PPD-IV may be the way to elucidate this argument. Mysterious issue is that GCPS and PHS appear in spite of having half amount of normal GLI3 protein, however, complete loss of normal Gli3 protein induces the similar phenotypes in mice. It has been speculated that truncated mutant GLI3/Gli3 protein might induce the phenotypes of GLI3/Gli3-related birth defects both in humans and mice.