PMC7327611_01
PMC7327611_02
Pedigree of the proband's family. Known results from family member MYLK. Testing and current clinical status are included.
CRIM2020-5108052.001.jpg
PMC7327611_02_CRIM2020-5108052.001.jpg
fig1
Taken together, this would constitute a negative variant as the large N-terminus may participate in binding and cause additional loss of function that a heteromeric individual's wild-type MYLK would be competing for binding (Figure 1); our modeling has previously supported such findings.
MYLK molecular model for the full-length human sequence consisting of 1914 amino acids and the variant p.S1218del. All protein residues shown are rendered in ribbons and colored by the domain map at the top. (a) Full-length model for the entire MYLK structure in ribbon is given and labeled by the domains in the key. (b) The p.S1218del structure for MYLK is shown and rendered similarly to that in panel (a). Colors in the domain legend key (top) match ribbon colors for both models shown.
CRIM2020-5108052.002.jpg
PMC7327611_02_CRIM2020-5108052.002.jpg
fig2
Additionally, significant loss of activity was seen due to the enzymatic region being cleaved from the protein's global structure (Figures 2 and 3).
MYLK electrostatic mapping for full length and truncation. (a) Full-length model for the entire MYLK structure with electrostatics calculated using Poisson-Boltzmann (PB) calculation overlaid onto the structure. The kinase domain is boxed to emphasize its position in the protein. (b) Variant p.S1218del MYLK model is given with electrostatics overlaid indicating changes in charge. Here, the deletion of the crucial kinase domain is shown. (c) As indicated in the boxed region, the secondary structure for the protein kinase domain region is shown (rotated 90  to emphasize the catalytic region (on top).
CRIM2020-5108052.003.jpg
PMC7327611_02_CRIM2020-5108052.003.jpg
fig3
Additionally, significant loss of activity was seen due to the enzymatic region being cleaved from the protein's global structure (Figures 2 and 3).