Figure 1.
A new multiplex kindred with WD and heterozygosity for a rare IRF4 variant. (A) Pedigree of the kindred, with allele segregation. Generations are designated by Roman numerals, and each individual is designated by an Arabic numeral (from left to right). Colors indicate clinical status for WD (black: affected, white: healthy). The proband is indicated by an arrow. M = mutated. (B) Magnetic resonance imaging (MRI) showing right sternoclavicular arthritis in P1. (C) WES analysis of P1 and P2. MAF = minor allele frequency; MSC = mutation significance cutoff. (D) IRF4 protein, with the DNA-binding domain (DBD) in red and the IRF association domain (IAD) in blue. Two variants are shown: the previously reported LOF WD variant p.R98W in blue and the newly identified IRF4 variant in red p.R25S. (E) Electropherogram of IRF4 genomic DNA sequences from a healthy unrelated control, two healthy related controls (I.1 and II.2), and the patients (P1 and P2). The variant results in the substitution of an adenine for a cytosine in exon 1 at nucleotide position 73 (c.73C > A), leading to the replacement of an arginine residue with a serine residue at amino acid position 25 (p.R25S). (F) In silico prediction for p.R25S variant on the quaternary structure of the IRF4/ISRE homodimer complex. Left panel: Ribbon representation of the overall IRF4/ISRE homodimer structure (PDB:7JM4) showing IRF4 (blue), IRF4 α-3-recognition helix (pink), and DNA (light red). Right upper panel: Close-up view of the p.R98 residue (pink) positioned within the α-3-recognition helix, forming hydrogen bonds (black dotted lines) with cytosine bases C11 and C10 of the DNA (light red). Right lower panel: Structural superposition of p.R25 residue (WT protein, blue) and the p.S25 (variant, red). The WT p.R25, located in the α-1 helix, forms a stabilizing hydrogen bond (black dotted lines) with residue p.D106 (blue) in the β3 sheet. The p.R25S is predicted to disrupt this interaction.

A new multiplex kindred with WD and heterozygosity for a rare IRF4 variant. (A) Pedigree of the kindred, with allele segregation. Generations are designated by Roman numerals, and each individual is designated by an Arabic numeral (from left to right). Colors indicate clinical status for WD (black: affected, white: healthy). The proband is indicated by an arrow. M = mutated. (B) Magnetic resonance imaging (MRI) showing right sternoclavicular arthritis in P1. (C) WES analysis of P1 and P2. MAF = minor allele frequency; MSC = mutation significance cutoff. (D) IRF4 protein, with the DNA-binding domain (DBD) in red and the IRF association domain (IAD) in blue. Two variants are shown: the previously reported LOF WD variant p.R98W in blue and the newly identified IRF4 variant in red p.R25S. (E) Electropherogram of IRF4 genomic DNA sequences from a healthy unrelated control, two healthy related controls (I.1 and II.2), and the patients (P1 and P2). The variant results in the substitution of an adenine for a cytosine in exon 1 at nucleotide position 73 (c.73C > A), leading to the replacement of an arginine residue with a serine residue at amino acid position 25 (p.R25S). (F) In silico prediction for p.R25S variant on the quaternary structure of the IRF4/ISRE homodimer complex. Left panel: Ribbon representation of the overall IRF4/ISRE homodimer structure (PDB:7JM4) showing IRF4 (blue), IRF4 α-3-recognition helix (pink), and DNA (light red). Right upper panel: Close-up view of the p.R98 residue (pink) positioned within the α-3-recognition helix, forming hydrogen bonds (black dotted lines) with cytosine bases C11 and C10 of the DNA (light red). Right lower panel: Structural superposition of p.R25 residue (WT protein, blue) and the p.S25 (variant, red). The WT p.R25, located in the α-1 helix, forms a stabilizing hydrogen bond (black dotted lines) with residue p.D106 (blue) in the β3 sheet. The p.R25S is predicted to disrupt this interaction.

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