title: The pleiotropic mouse phenotype extra-toes spotting is caused by translation initiation factor Eif3c mutations and is associated with disrupted sonic hedgehog signaling.
abstract: Polydactyly is a common malformation and can be an isolated anomaly or part of a pleiotropic syndrome. The elucidation of the mutated genes that cause polydactyly provides insight into limb development pathways. The extra-toes spotting (Xs) mouse phenotype manifests anterior polydactyly, predominantly in the forelimbs, with ventral hypopigmenation. The mapping of Xs(J) to chromosome 7 was confirmed, and the interval was narrowed to 322 kb using intersubspecific crosses. Two mutations were identified in eukaryotic translation initiation factor 3 subunit C (Eif3c). An Eif3c c.907C>T mutation (p.Arg303X) was identified in Xs(J), and a c.1702_1758del mutation (p.Leu568_Leu586del) was identified in extra-toes spotting-like (Xsl), an allele of Xs(J). The effect of the Xs(J) mutation on the SHH/GLI3 pathway was analyzed by in situ hybridization analysis, and we show that Xs mouse embryos have ectopic Shh and Ptch1 expression in the anterior limb. In addition, anterior limb buds show aberrant Gli3 processing, consistent with perturbed SHH/GLI3 signaling. Based on the occurrence of Eif3c mutations in 2 Xs lines and haploinsufficiency of the Xs(J) allele, we conclude that the Xs phenotype is caused by a mutation in Eif3c, a component of the translation initiation complex, and that the phenotype is associated with aberrant SHH/GLI3 signaling.
authors.affiliation: Institute for Biomedical Sciences, George Washington University, Washington, District of Columbia, USA.
authors.forename: Derek E
authors.initials: DE
authors.lastname: Gildea
authors.forename: Erin S
authors.initials: ES
authors.lastname: Luetkemeier
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Bao
authors.forename: Stacie K
authors.initials: SK
authors.lastname: Loftus
authors.forename: Susan
authors.initials: S
authors.lastname: Mackem
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Yang
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
mesh_terms: D000818:Animals; D015153:Blotting, Western; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics* / Q000378:metabolism*; D005838:Genotype; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010641:Phenotype; D017689:Polydactyly / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000074290:Zinc Finger Protein Gli3
chemical_list: D039621:Eukaryotic Initiation Factor-3; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D000074290:Zinc Finger Protein Gli3