Figure 5

Location of variants in six protein structures. A-B describe two causative variants, C-D demonstrate two predicted deleterious variants, E-F illustrate two predicted deleterious variants whose clinical associations are inconclusive. For all figures, the representations are as follows: ribbon for proteins, ball and stick for ligands, mesh for ligand binding sites, and sphere for amino acid variants. Amino acid variants caused by homozygous or heterozygous nsSNPs are indicated as (***) or (*), respectively. Additional variants that are known to be associated with diseases (D), or affect protein functionality (F), and/or stability (S) are also identified. A: Apolipoprotein E (PDB:2L7B). B: Myotubularin-related protein 2 (PDB:1LW3). C: Thrombospondin-1 (PDB:1UX6 and homology model). Residues 1–548 are missing from the structure, residues 549–829 (brown ribbons) are modeled from human THBS2 (PDB:1YO8), residues 848–1169 (white ribbons) are from a crystal structure of THBS1 (PDB:1UX6). Coordination complexes of amino acid side chains and Ca²⁺ ions (green spheres) as seen in the crystal structures are indicated with purple lines. The Ca²⁺ ions with unidentified coordination complexes are derived from the superposition of Ca²⁺ ions in 1YO8 onto the homology model. D: Acidic mammalian chitinase (PDB:3FY1). Three homozygous nsSNPs were also identified from the same genome, but only two are present in the crystal structure. E: Myosin heavy chain 6 (αMyHC) modeled from Myosin heavy chain 7 (βMyHC) (PDB:4DB1). The C-terminal (residues 778–1939) is missing from the template crystal structure. F: Pancreatic alpha-amylase (AMY2A) (PDB:3OLE). The Pro145 is located at the end of the extended β-loop and is part of a binding site for α-D-glucose. For clarity, only one α-D-glucose binding site is shown. Other variants known to affect the enzymatic activities are located around the chloride ion (green sphere) in the central vicinity of the protein.