GLI3 and the Pallister–Hall and Greig Cephalopolysyndactyly Syndromes

Abstract

Abstract Pallister–Hall syndrome (PHS) and Greig cephalopolysyndactyly syndrome (GCPS) are distinct, pleiotropic developmental anomaly syndromes that are caused by mutations in GLI3 and inherited in an autosomal dominant pattern. The major anomalies in PHS include hypothalamic hamartoma, central or postaxial polydactyly, and airway anomalies. The major anomalies of GCPS include macrocephaly with hypertelorism and preor postaxial polydactyly. Both disorders have a wide spectrum of severity but are clinically distinct. The GLI3 gene encodes a C2H2-type zinc 7nger transcription factor that is downstream in the sonic hedgehog (SHH) signaling pathway. The mutational spectrum of GLI3 mutations in patients with GCPS is broad, including translocations, gross and molecular deletions, amino acid substitutions, and frameshift and nonsense mutations. The mutational spectrum of PHS typically comprises only frameshift mutations that preserve the zinc 7nger binding domain of GLI3. A hypothesis has been proposed to explain the correlation of these two phenotypes and the associated mutations.