The pleiotropic mouse phenotype extra-toes spotting is caused by translation initiation factor Eif3c mutations and is associated with disrupted sonic hedgehog signaling

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 XsJ 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 XsJ, and a c.1702_1758del mutation (p.Leu568_Leu586del) was identified in extra-toes spotting-like (Xsl), an allele of XsJ. The effect of the XsJ 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 XsJ 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.—Gildea, D. E., Luetkemeier, E. S., Bao, X., Loftus, S. K., Mackem, S., Yang, Y., Pavan, W. J., Biesecker, L. G. The pleiotropic mouse phenotype extra-toes spotting is caused by translation initiation factor Eif3c mutations and is associated with disrupted sonic hedgehog signaling

Consent codes: upholding standard data use conditions

A systematic way of recording data use conditions that are based on consent permissions as found in the datasets of the main public genome archives (NCBI dbGaP and EMBL-EBI/CRG EGA).SOMD is supported by the Canadian Institutes of Health Research (grants EP1-120608; EP2-120609), the Canada Research Chair in Law and Medicine, and the Public Population Project in Genomics and Society (P3G). DNP and ESL are supported, in part, by the Intramural Research Program of the NIH, Office of the Director, Office of Science Policy. BMK is supported by the Canada Research Chairs Program. MT and MR are sponsored by ODEX4all (NWO 650.002.002) and funding from the European Commission (FP-7 project RD-Connect, grant agreement No. 305444

Data use categories and requirements (Consent Codes): definition and abbreviation.

<p>Data use categories and requirements (Consent Codes): definition and abbreviation.</p