Fig. 3

The structure of the missense pathogenic variant in the amino acid sequence between the TB7 and TB8 domains was analyzed (AA 1500–2119). The variant p.Cys1791Ser found in the EGF-like domains 29 interferes with the formation of a disulfide bond between the two cysteines. (Residues 1777 and 1791 were highlighted in blue space filling mode.) The new pathogenic variant p.Cys1791Ser (panel B) causes an 8 per cent lengthening of the region between the TB6 and TB8 domains. The total length of the analyzed amino acid fragment changes from 126.80 Å in the wild-type protein to 136.70 Å in the mutant protein. The effect of the new variant is comparable to that of the variant p.Cys1791Phe (panel C), which causes an elongation of the analyzed region. The amino acidic changes to Thr and Arg (panels E and F) appear to be the least tolerated. These two pathogenic variants caused TB8 module misfolding with a rotation of about 90°, as indicated by the yellow circle. The final variant, p.Cys1791Tyr (panel D), appears to have no effect on protein length while causing a critical misfolding of the EGF-like 29 domain