Figure 1.
Rare monoallelic variants in THPO are associated with thrombocytopenia. (A) Associations between rare filtered variants across all genes and case/control groups defined by the presence of thrombocytopenia were inferred using the BeviMed method. Genes with a posterior probability of association >0.4 are shown for dominant and recessive inheritance models. Genes previously associated with thrombocytopenia are shown as blue symbols, whereas those with no confirmed association are shown as gray symbols. (B) Pedigree structures of the 3 index cases (A, II.2; B, I.2; and C, II.1) and pedigree members, indicating the presence (black symbols) or absence (white symbols) of thrombocytopenia and cases with unknown PLT (gray symbols). Genotypes confirmed by Sanger sequencing are annotated against canonical transcript ENST00000204615.7 (GRCh37.p13). wt/wt indicates homozygous for the reference allele. wt/* indicates the monoallelic variant. (C) Schematic diagram of the wt and predicted variant TPO proteins with amino acid numbering indicating the signal peptide (1-21), RBD (22-152), and C-terminal domain (153-353). Black circles indicate the position of consensus N-linked glycan sites. The insertion variants p.E204fs*123 and p.L269Pfs*58 (*) predict altered amino acid sequence (shaded region) downstream of the variant site and chain truncation, both after codon 327. The predicted p.R99W variant (*) is in the RBD. (D) Phylogenetic conservation of R99 across representative mammalian species shown in a sequence line up prepared using Clustal Omega. (E) Ribbon diagram of the TPO RBD derived from PDB:1V7M with direct contact regions between TPO and the TPO receptor indicated in red and the 4 helical regions indicated as A, B, C, and D. In the expanded view (left panel) and detailed vertical view (right panel), the wt R99 (green side chain) occurs in the cross-over region between helices A and B in the wt TPO peptide. Substitution of R99 with a W (blue) residue introduces a amphipathic residue with a bulky aromatic side chain into the space between helices B and C.

Rare monoallelic variants in THPO are associated with thrombocytopenia. (A) Associations between rare filtered variants across all genes and case/control groups defined by the presence of thrombocytopenia were inferred using the BeviMed method. Genes with a posterior probability of association >0.4 are shown for dominant and recessive inheritance models. Genes previously associated with thrombocytopenia are shown as blue symbols, whereas those with no confirmed association are shown as gray symbols. (B) Pedigree structures of the 3 index cases (A, II.2; B, I.2; and C, II.1) and pedigree members, indicating the presence (black symbols) or absence (white symbols) of thrombocytopenia and cases with unknown PLT (gray symbols). Genotypes confirmed by Sanger sequencing are annotated against canonical transcript ENST00000204615.7 (GRCh37.p13). wt/wt indicates homozygous for the reference allele. wt/* indicates the monoallelic variant. (C) Schematic diagram of the wt and predicted variant TPO proteins with amino acid numbering indicating the signal peptide (1-21), RBD (22-152), and C-terminal domain (153-353). Black circles indicate the position of consensus N-linked glycan sites. The insertion variants p.E204fs*123 and p.L269Pfs*58 (*) predict altered amino acid sequence (shaded region) downstream of the variant site and chain truncation, both after codon 327. The predicted p.R99W variant (*) is in the RBD. (D) Phylogenetic conservation of R99 across representative mammalian species shown in a sequence line up prepared using Clustal Omega. (E) Ribbon diagram of the TPO RBD derived from PDB:1V7M with direct contact regions between TPO and the TPO receptor indicated in red and the 4 helical regions indicated as A, B, C, and D. In the expanded view (left panel) and detailed vertical view (right panel), the wt R99 (green side chain) occurs in the cross-over region between helices A and B in the wt TPO peptide. Substitution of R99 with a W (blue) residue introduces a amphipathic residue with a bulky aromatic side chain into the space between helices B and C.

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