The molecular basis of Pallister-Hall associated polydactyly

Mutations in GL13 manifest in several distinct clinical phenotypes including Greig cephalopolysyndactyly syndrome and Pallister-Hall syndrome (PHS). GL13 belongs to the GLI family of transcription factors that mediates extracellular Sonic hedgehog (SHH) signals. In the absence of SHH signals, GL13 is processed to form a transcriptional repressor termed GL13R. During early limb development, the regulation of GL13 processing by SHH is decisive in determining the correct number and identity of digits. Analyses of mouse embryos have produced evidence that elevated levels of GL13R reduce the number of developing digits. Remarkably, PHS causative mutations are predicted to produce a truncated protein similar to the endogenous GL13R. Nevertheless, pollydactyly is frequently observed in PHS patients and it even represents a criterion for the clinical diagnosis of PHS. In order to detect the underlying cause of this obvious discrepancy, we made use of the GH3 A699 mouse mutant, which represents the mouse model of PHS. We show that the mutant murine allele gives rise to a truncated version of GL13 that mimicks both the processed GL13R isoform and the proposed pathogenic GL13(PHS) protein. We analyzed how the mutant GL13 protein interferes with the anteroposterior patterning of early limb development, whereas processes that are associated with the outgrowth of the limb bud remain remarkably unimpaired. The presented findings help to understand the previously enigmatic emergence of Pallister-Hall associated polydactyly and thus add to the understanding of the pathogenic mode of the action of GL13(PHS).