case_images: PMC10571918_01
case_images: PMC10571918_02
case_images: PMC10571918_03
case_images: PMC10571918_04
case_images: PMC10571918_05
case_images: Parental and proband SMN1 genotypes. The father (blue) has two copies of SMN1 without the c.796T>C variant or the g.27134T>G polymorphism (1+1 or 2+0). The mother (orange) has a cis-oriented SMN1 duplication with the homozygous c.796T>C variant (marked by "*") on one allele and a wild-type SMN1 on the other allele (2*+1). The proband has a cis-oriented SMN1 duplication with the homozygous c.796T>C variant on one allele and a null SMN1 on the other allele (2*+0). The proband's null SMN1 on the paternal chromosome was presumed to have arisen from a de novo deletion. Alternatively, the father may also be a 2+0 carrier, but is without the g.27134T>G polymorphism.
case_images: fncel-17-1259380-g001.jpg
case_images: PMC10571918_05_fncel-17-1259380-g001.jpg
case_images: fig1
case_images: Parental analysis of the mother revealed a complex genotype (2*+1):with three copies of SMN1, heterozygous for the c.796T>C variant, and also carrying the g.27134T>G polymorphism (Figure 1). A detailed depiction of the parental and proband genotypes is provided in Supplementary Figure S1. The father also has only one copy of SMN2 (Figure 1; Supplementary Figure S1). Alternatively, the father may also be a 2+0 carrier, but is without the g.27134T>G polymorphism (Figure 1; Supplementary Figure S1).
case_images: Structures of human wild-type and mutant SMN YG-box (residues 255-281) tetramers. Ser266 in the wild-type peptide and Pro266 in the mutant peptide are shown in ball-and-stick representations. Predicted solution structures of the wild-type YG-box tetramer (A, golden/wheat) and the mutant tetramer (B, blue/cyan). Root mean squared fluctuations of the helix backbones in the wild-type YG-box (C) and the mutant YG-box (D) from molecular dynamics simulations. The vertical dotted lines indicate the location of the substitution. The error bars indicate standard deviations. A kink is noticeable in the mutant peptide but not in the wild-type peptide.
case_images: fncel-17-1259380-g002.jpg
case_images: PMC10571918_05_fncel-17-1259380-g002.jpg
case_images: fig2
case_images: Microsecond dynamics simulations indicated that the Ser266Pro YG-box helix structure becomes disordered, especially in the tetramer complex (Figure 2). Furthermore, proline is a known helix breaker, and a kink in the YG-box at position 266 is predicted to profoundly alter the wild-type SMN structure (Figure 2).