case_images: PMC10936578_01
case_images: The clinical diagnosis of the proband. (A) Family diagram of patients with disease, and the arrow shows the proband. (B) The morphology of the patient's feet has significantly high arches. (C) The patient has calf muscle atrophy.
case_images: fneur-15-1319962-g001.jpg
case_images: PMC10936578_01_fneur-15-1319962-g001.jpg
case_images: fig1
case_images: The family, including seven people were investigated in this study (Figure 1A). Both Achilles tendon reflex and knee-jerk reflex are diminished, and there is a decrease in pinprick sensation (Figures 1B,C).
case_images: Gene and protein analysis. (A) Sanger sequencing results for I-1 (unaffected +/+), II-3 (affected +/-), and III-1 (affected +/-) patients (see Figure 1A for pedigree). (B) Predicted residue tolerance in the MPZ protein obtained using MetaDome. H49 is predicted to be of neutral tolerance to mutations. MPZ contains two domains: immunoglobulin-like domain of protein zero (IgV_P0) and Myelin-PO glycoprotein cytoplasmic C-term (Myelin-PO_C) by Conserved Domain Search prediction. (C) H49 is located on the IgV_P0 domain shown on the full length MPZ model (left panel). The atomic conformation (middle panels) and the surface electrostatic potential energy (right panels) change with the H49N variant. In the middle panels, blue "A" and "B" indicate 2 conformations of H49 in the crystal structure. Yellow line and text indicate the distance between atoms on side chains at positions 35 and 49 (angstrom). The blue and red atoms represent negative and positive charges, respectively. The variation of H49N causes the side chain charge from negative to become neutral. In the right panels, red means positive, blue means negative, and white means neutral. The surface potential prediction is slight changed from positive to neutral.
case_images: fneur-15-1319962-g002.jpg
case_images: PMC10936578_01_fneur-15-1319962-g002.jpg
case_images: fig2
case_images: Sanger sequencing further confirmed the co-segregation of this variant with the affected family members (Figure 2A) and its absence in our 200 control cohorts. This novel variant, resulting in the substitution of histidine with asparagine, was located at a neutral tolerant site and Immunoglobulin-like domain of protein zero (IgV_P0) (Figure 2B). We predicted and compared the protein structure after the p.His49Asn variant (Figure 2C), based on the latest reports of IgV_P0 domain (PDBid: 8iia). Surface potential analysis additionally revealed that variant altered the surface charge of the MPZ protein (Figure 2C).