Bioinformatic analysis of human ZPR1 gene pathogenic exome mutations

Abstract

Advanced sequencing technologies enable rapid detection of sequence variants, aiming to uncover the molecular foundations of human genetic disorders. The challenge lies in interpreting the influence of new exome variants that lead to diverse phenotypes. Our study introduces a detailed, multi-tiered method for assessing the impact of novel variants, particularly focusing on the zinc finger protein 1 (ZPR1) gene. Herein, we employed a combination of variant effect predictors, protein stability analyses, and the American College of Medical Genetics and Association of Molecular Pathology (ACMG/AMP) guidelines. Our structural analysis pinpoints specific amino acid residues in the ZPR1 zinc finger domains that are sensitive to changes, distinguishing between benign and disease-causing coding variants using rigorous in silico tools. We examined 223 germline ZPR1 exome variants, uncovering significant ethnic disparities in the frequency of heterozygous harmful ZPR1 variants, ranging from 0.04% in the Ashkenazi Jewish population to 0.34% in African/African Americans. Additionally, the discovery of three homozygous carriers in European and South Asian groups suggests a higher occurrence of ZPR1 variants in these demographics, meriting further exploration. This research provides insights into the prevalence and implications of amino acid substitutions in the ZPR1 protein.

Fig 1.

ZPR1 protein model generated with the software PROTTER [57]. This model indicates the locations of ancestral amino acids, including the location of the pathogenic ZEMs.

Fig 2.

The distribution of pathogenic variants among different ethnic groups in at least five individuals.

Fig 3.

The 3D structure model for ZPR1 protein (Uniprot code: AF-O75312-F1). The structure is colored from N-ter (blue) to C-ter (red). The mutated residues with ΔΔG >= 1.5 kcal/mol are labeled. The figure was generated using ChimeraX [58]. The color range is determined by five color wells, which correspond to the starting color, three intermediate interpolation colors, and the ending color from blue (N-terminal), cyan, green, yellow, and red (C-terminal), in that order. α-helices = cylinders β-strands = arrows where arrowheads points in the N-terminus to C-terminus direction non alpha/beta structures = threads or strings