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AJMA_33903_sm_Suppl-Fig-1.tif369KFig. 1: A multiple alignment (NCBI COBALT) comparison of related sequences obtained by a protein BLAST search ( was generated of the N-terminal Regulatory motif (NR in red, see [29]) consisting of the Degron N motif [30]and SUFU binding site (in green) as arranged by GLI 1, 2 or 3 family types. Aminoacid differences from the top reference line are indicated by the symbol "X". Interestingly, all detected mis-sense changes (highlighted by an orange arrow) 1) c.677G>A (p.Arg226His) 2) the putative SNP c.686G>T (p.Arg229Leu) and 3) the c.691 C>T (p.Arg231Trp) occur at residues conserved in all examples of vertebrate Gli2 and Gli3 protein sequences. Within the GLI1 family the orange marked ("X") residues are the similarly charges aminoacid Lys. Taken together, the similar conservation properties of all three examples does not allow for a clear distinction between likely mutations (p.Arg226His) and (p.Arg231Trp) and rare population variants seen in normal individuals (p.Arg229Leu).
AJMA_33903_sm_Suppl-Table-I.doc50KTable I: Summary of the variants identified in GLI2 [RefSeq ID: NM_005270] exon 6 (c.644_845) normal control genotypes. Neither the c.677G>A (the variant in the family described here) nor the c.691 C>T (a variant found in an unrelated proband with HPE) changes were found in 1096 human control chromosomes by direct sequencing. The c.677G>A variant was also not found in 928 human control chromosomes by TaqMan assay.

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