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The molecular basis of Pallister Hall associated polydactyly.
Hum Mol Genet. 2007 Sep 01; 16(17):2089-96.HM

Abstract

Mutations in GLI3 manifest in several distinct clinical phenotypes including Greig cephalopolysyndactyly syndrome and Pallister-Hall syndrome (PHS). GLI3 belongs to the GLI family of transcription factors that mediates extracellular Sonic hedgehog (SHH) signals. In the absence of SHH signals, GLI3 is processed to form a transcriptional repressor termed GLI3R. During early limb development, the regulation of GLI3 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 GLI3R reduce the number of developing digits. Remarkably, PHS causative mutations are predicted to produce a truncated protein similar to the endogenous GLI3R. Nevertheless, polydactyly 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 Gli3(Delta699) mouse mutant, which represents the mouse model of PHS. We show that the mutant murine allele gives rise to a truncated version of GLI3 that mimicks both the processed GLI3R isoform and the proposed pathogenic GLI3(PHS) protein. We analyzed how the mutant GLI3 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 GLI3(PHS).

Authors+Show Affiliations

Institut für Entwicklungs- und Molekularbiologie der Tiere, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17588959

Citation

Hill, Patrick, et al. "The Molecular Basis of Pallister Hall Associated Polydactyly." Human Molecular Genetics, vol. 16, no. 17, 2007, pp. 2089-96.
Hill P, Wang B, Rüther U. The molecular basis of Pallister Hall associated polydactyly. Hum Mol Genet. 2007;16(17):2089-96.
Hill, P., Wang, B., & Rüther, U. (2007). The molecular basis of Pallister Hall associated polydactyly. Human Molecular Genetics, 16(17), 2089-96.
Hill P, Wang B, Rüther U. The Molecular Basis of Pallister Hall Associated Polydactyly. Hum Mol Genet. 2007 Sep 1;16(17):2089-96. PubMed PMID: 17588959.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The molecular basis of Pallister Hall associated polydactyly. AU - Hill,Patrick, AU - Wang,Baolin, AU - Rüther,Ulrich, Y1 - 2007/06/22/ PY - 2007/6/26/pubmed PY - 2008/1/10/medline PY - 2007/6/26/entrez SP - 2089 EP - 96 JF - Human molecular genetics JO - Hum Mol Genet VL - 16 IS - 17 N2 - Mutations in GLI3 manifest in several distinct clinical phenotypes including Greig cephalopolysyndactyly syndrome and Pallister-Hall syndrome (PHS). GLI3 belongs to the GLI family of transcription factors that mediates extracellular Sonic hedgehog (SHH) signals. In the absence of SHH signals, GLI3 is processed to form a transcriptional repressor termed GLI3R. During early limb development, the regulation of GLI3 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 GLI3R reduce the number of developing digits. Remarkably, PHS causative mutations are predicted to produce a truncated protein similar to the endogenous GLI3R. Nevertheless, polydactyly 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 Gli3(Delta699) mouse mutant, which represents the mouse model of PHS. We show that the mutant murine allele gives rise to a truncated version of GLI3 that mimicks both the processed GLI3R isoform and the proposed pathogenic GLI3(PHS) protein. We analyzed how the mutant GLI3 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 GLI3(PHS). SN - 0964-6906 UR - https://www.unboundmedicine.com/medline/citation/17588959/The_molecular_basis_of_Pallister_Hall_associated_polydactyly_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddm156 DB - PRIME DP - Unbound Medicine ER -