Figure 3.
Effect sizes for variants in platelet disorder genes and MPL structure. (A) Effect sizes (in SD) for the platelet count (PLT) and MPV in carriers of 128 BPTD-variants present in at least 5 unrelated European UKB participants; 24 variants labeled by HGNC gene symbol have a significant effect on PLT and/or MPV (P < .05). Variants are color-coded by MOI for the associated platelet disorder: AD, autosomal dominant; AR, autosomal recessive; XL, X-linked inheritance. (B) Effect sizes in SD with 95% confidence intervals (CI) for platelet count and MPV associated with 19 cataloged-variants for AD thrombocytopenia disorders, of which 10 have significant effects (P < .05). Variants with AD MOI are in blue and AD/AR in brown. MDT decision is indicated by circles and squares for accept and reject, respectively. (C) Effect sizes in SD with 95% CI values for platelet count and MPV that are significantly associated with 14 cataloged-variants for AR platelet disorders (P < .05). Circles, squares and triangles indicate MDT decisions for accept, reject and undecided, respectively. (D) Violin plots with platelet count distributions of UKB controls (black), carriers of 1 of 5 CAMT-causing MPL variants that were associated with a significant increase in platelet count (purple) and patients with CAMT (red); each point represents a unique UKB individual, except for the CAMT cases for whom platelet count values were retrieved from the NIHR BioResource study database. (E) Probable structure of the MPL receptor and its ligand thrombopoietin (TPO), as represented by the 3D structure of the highly homologous erythropoietin receptor (EPOR, chains B and C) and bound erythropoietin (EPO, chain A) from the Protein Data Bank (PDB) entry “1EER,” which is the best available model for the impact of MPL residue changes. Left: PyMOL image of the 1eer structure with 3 variants shown in spacefill on chains B and C. Two are possible LoF variants, Arg102Pro, labeled R102 on chain C and shown in red, and Gly131Ser, labeled G131, orange; and 1 predicted as benign, Arg90Gln, labeled R90, magenta. In brackets are the residue numbers in the “1EER”structure. Right: schematic representation of the complex, with the same colors for the domains and variants (small, colored circles). Additional variants with possible functional consequences and which, like the LoF variant Gly131Ser, are highly conserved and occur in the linker region between the domains are: Pro136Arg, Pro136His and Gly131Ser (not shown). FD, fibronectin type III domain; LBD, ligand-binding domain.

Effect sizes for variants in platelet disorder genes and MPL structure. (A) Effect sizes (in SD) for the platelet count (PLT) and MPV in carriers of 128 BPTD-variants present in at least 5 unrelated European UKB participants; 24 variants labeled by HGNC gene symbol have a significant effect on PLT and/or MPV (P < .05). Variants are color-coded by MOI for the associated platelet disorder: AD, autosomal dominant; AR, autosomal recessive; XL, X-linked inheritance. (B) Effect sizes in SD with 95% confidence intervals (CI) for platelet count and MPV associated with 19 cataloged-variants for AD thrombocytopenia disorders, of which 10 have significant effects (P < .05). Variants with AD MOI are in blue and AD/AR in brown. MDT decision is indicated by circles and squares for accept and reject, respectively. (C) Effect sizes in SD with 95% CI values for platelet count and MPV that are significantly associated with 14 cataloged-variants for AR platelet disorders (P < .05). Circles, squares and triangles indicate MDT decisions for accept, reject and undecided, respectively. (D) Violin plots with platelet count distributions of UKB controls (black), carriers of 1 of 5 CAMT-causing MPL variants that were associated with a significant increase in platelet count (purple) and patients with CAMT (red); each point represents a unique UKB individual, except for the CAMT cases for whom platelet count values were retrieved from the NIHR BioResource study database. (E) Probable structure of the MPL receptor and its ligand thrombopoietin (TPO), as represented by the 3D structure of the highly homologous erythropoietin receptor (EPOR, chains B and C) and bound erythropoietin (EPO, chain A) from the Protein Data Bank (PDB) entry “1EER,” which is the best available model for the impact of MPL residue changes. Left: PyMOL image of the 1eer structure with 3 variants shown in spacefill on chains B and C. Two are possible LoF variants, Arg102Pro, labeled R102 on chain C and shown in red, and Gly131Ser, labeled G131, orange; and 1 predicted as benign, Arg90Gln, labeled R90, magenta. In brackets are the residue numbers in the “1EER”structure. Right: schematic representation of the complex, with the same colors for the domains and variants (small, colored circles). Additional variants with possible functional consequences and which, like the LoF variant Gly131Ser, are highly conserved and occur in the linker region between the domains are: Pro136Arg, Pro136His and Gly131Ser (not shown). FD, fibronectin type III domain; LBD, ligand-binding domain.

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