The Phenotypic Spectrum of GLI3 Morphopathies Includes Autosomal Dominant Preaxial Polydactyly Type-IV and Postaxial Polydactyly Type-A/B; No Phenotype Prediction from the Position of GLI3 Mutations

Abstract

Functional characterization of a gene often requires the discovery of the full spectrum of its associated phenotypes. Mutations in the human GLI3 gene have been identified in Greig cepalopolysyndactyly, Pallister-Hall syndrome (PHS), and postaxial polydactyly type-A (PAP-A). We studied the involvement of GLI3 in additional phenotypes of digital abnormalities in one family (UR003) with preaxial polydactyly type-IV (PPD-IV), three families (UR014, UR015, and UR016) with dominant PAP-A/B (with PPD-A and -B in the same family), and one family with PHS. Linkage analysis showed no recombination with GLI3-linked polymorphisms. Family UR003 had a 1-nt frameshift insertion, resulting in a truncated protein of 1,245 amino acids. A frameshift mutation due to a 1-nt deletion was found in family UR014, resulting in a truncated protein of 1,280 amino acids. Family UR015 had a nonsense mutation, R643X, and family UR016 had a missense mutation, G727R, in a highly conserved amino acid of domain 3. The patient with PHS had a nonsense mutation, E1147X. These results add two phenotypes to the phenotypic spectrum caused by GLI3 mutations: the combined PAP-A/B and PPD-IV. These mutations do not support the suggested association between the mutations in GLI3 and the resulting phenotypes. We propose that all phenotypes associated with GLI3 mutations be called "GLI3 morphopathies," since the phenotypic borders of the resulting syndromes are not well defined and there is no apparent genotype-phenotype correlation.

Classification and Developmental Biology of Congenital Anomalies of the Hand and Upper Extremity

“…Mutations in the limb-specific SHH regulatory region are responsible for preaxial polydactyly or triphalangeal thumb 113,114 . Defects in Gli3, an antagonist of SHH, are linked to both radial and ulnar polydactyly, implicating overexpression of SHH in both forms of polydactyly 115 . However, polydactyly is likely more complicated than simple overexpression of SHH since mutations in a variety of other genes that appear unrelated to the SHH pathway are also linked to polydactyly.…”

GLI3 is rarely implicated in OFD syndromes with midline abnormalities

“…Three types of apparently isolated polydactyly-PAP-A, PAP-A/B, and PPD-IV-are also caused by GLI3 mutations [Radhakrishna et al, 1997[Radhakrishna et al, , 1999. The major clinical findings of PHS include hypothalamic hamartoma, central and postaxial polydactyly, bifid epiglottis, imperforate anus, and renal abnormalities [Biesecker, 1993].…”

The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis

“…Besides, some cases of nonsyndromic PPDs have been reported in association with GLI3 mutations (OMIM#165240). 15,16 GLI3 is responsible for Greig cephalopolysyndactyly syndrome (GCPS, OMIM#175700) and Pallister-Hall Syndrome (PHS, OMIM#146510). GCPS can be very variable but usually presents with crossed polysyndactyly (PPD of lower limbs and postaxial polydactyly of upper limbs), macrocephaly, corpus callosum agenesis and sometimes craniosynostosis.…”