Pallister-Hall syndrome is a very rare autosomal dominant genetic disorder due to mutation in GLI3 gene in the short arm of chromosome 7 with variable penetrance and expressivity.
A robust gene-phenotype relationship between GLI3 and Greig cephalopolysyndactyly syndrome and Pallister-Hall syndrome has been well elucidated, and less is known about GLI3 mutation-caused isolated polydactyly.
Mutations in different domains of the GLI3 gene underlie several congenital diseases including Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS).
Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases).
Genotype/phenotype correlations have led to fine mapping of GLI3 and the recognition that PHS is caused by dominant negative mutations in the middle third of the gene.
GLI3 plays a predominant role in the pathogenesis of syndromic polydactyly: mutations have been identified in 68% of patients with Greig cephalopolysyndactyly syndrome and 91% of patients with Pallister-Hall syndrome.
The most important issue might be that GCPS and PHS exhibit an autosomal dominant trait, but mouse homologs, such as Pdn/Pdn, Xt(H)/Xt(H), Xt(J)/Xt(J) and Gli3(tmlUrt)/Gli3(tmlUrt), are autosomal recessive traits in the manifestation of similar phenotypes to human diseases.
The urogenital and anorectal abnormalities associated with PHS might be related to dysregulation of SHH signaling caused by GLI3 mutations rather than hormonal aberrations.
Mutations that lead to loss of function of the protein and to haploinsufficiency cause GCPS, while truncating mutations that result in constitutive repressor function of GLI3 lead to PHS.
Here, we report that cochleae from a mouse model of PHS (Gli3(Delta699)), which produces only the truncated, repressor form of GLI3, have a variably penetrant phenotype that includes an increase in the size of the sensory epithelium and the development of large ectopic sensory patches in Kölliker's organ (KO).