Novel pathogenic WHRN variant causing hearing loss in a moroccan family.

OBJECTIVES: The most prevalent sensory disease in humans is deafness. A variety of genes have been linked to hearing loss, which can either be isolated (non-syndromic) or associated with lesions in other organs (syndromic). It has been discovered that WHRN variants are responsible for non-syndromic hearing loss and Usher syndrome type II. METHODS AND RESULTS: Exome sequencing in a consanguineous Moroccan patient with severe hearing loss identified a single homozygous mutation c.619G > T; p.Ala207Ser in WHRN, encoding a cytoskeletal scaffold protein that binds membrane protein complexes to the cytoskeleton in ocular photoreceptors and ear hair cell stereocilia. Bioinformatics methods and molecular dynamic modeling were able to predict the pathogenic implications of this variation. CONCLUSION: We used whole exome sequencing to find a homozygous WHRN gene variant in a Moroccan family. Numerous bioinformatics methods predict that this modification might result in a change in the WHRN protein's structure.

Exploring the impact of CYP11A1's missense SNPs on the interaction between CYP11A1 and cholesterol: A comprehensive structural analysis and MD simulation study.

The process of steroidogenesis plays a vital role in human physiology as it governs the biosynthesis of mineralocorticoids, glucocorticoids, and androgens. These three classes of steroid hormones are primarily produced in the adrenal and gonadal glands through steroidogenesis pathways. Initiated by the side chain cleavage of cholesterol (CLR), this process leads to the conversion of cholesterol into pregnenolone and isocaproic aldehyde. The enzyme CYP11A1, encoded by the CYP11A1 gene, plays a key role in catalyzing the side chain cleavage of CLR. Several single nucleotide polymorphisms (SNPs) have been identified in the CYP11A1 gene, which may predispose carriers to disorders associated with abnormal steroidogenesis. Specifically, missense SNPs in the CYP11A1 gene have the potential to negatively impact the interaction between CYP11A1 and CLR, thus affecting the overall metabolome of steroid hormones. In this computational study, we focused on a specific set of missense SNPs reported in the CYP11A1 gene, aiming to identify variants that directly impact the interaction between CYP11A1 and CLR. The three-dimensional structure of the CYP11A1-CLR complex was obtained from the RCSB Protein Data Bank, while missense SNPs in the CYP11A1 gene were retrieved from Ensembl. To predict the most deleterious variants, we utilized the ConSurf server, SIFT, and PolyPhen. Furthermore, we assessed the impact of induced amino acid (AA) substitutions on the CYP11A1-CLR interaction using the PRODIGY server, PyMol, and Ligplot programs. Additionally, molecular dynamics (MD) simulations were conducted to analyze the effects of deleterious variants on the structural dynamics of the CYP11A1-CLR complex. Among the 8096 retrieved variants, we identified ten missense SNPs (E91K, W147G, R151W, R151Q, S391C, V392M, Q395K, Q416E, R460W, and R460Q) as deleterious for the interaction between CYP11A1 and CLR. MD simulations of the CYP11A1-CLR complexes carrying these deleterious AA substitutions revealed that Q416E, W147G, R460Q, and R460W had the most pronounced impacts on the structural dynamics of the complex. Consequently, these missense SNPs were considered the most deleterious ones. Further functional tests are recommended to assess the impact of these four missense SNPs on the enzymatic activity of CYP11A1. Moreover, Genome-Wide Association Studies (GWAS) should be conducted to determine the significance of their association with abnormal steroidogenesis diseases in various patient groups.

In silico exploration and molecular dynamics of deleterious SNPs on the human TERF1 protein triggering male infertility.

By limiting chromosome erosion and end-to-end fusions, telomere integrity is critical for chromosome stability and cell survival. During mitotic cycles or due to environmental stresses, telomeres become progressively shorter and dysfunctional, thus triggering cellular senescence, genomic instability and cell death. To avoid such consequences, the telomerase action, as well as the Shelterin and CST complexes, assure the telomere's protection. Telomeric repeat binding factor 1 (TERF1), which is one of the primary components of the Shelterin complex, binds directly to the telomere and controls its length and function by regulating the telomerase activity. Several reports about TERF1 gene variations have been associated with different diseases, and some of them have linked these variations to male infertility. Hence, this paper can be advantageous to investigate the association between the missense variants of the TERF1 gene and the susceptibility to male infertility. The stepwise prediction of SNPs pathogenicity followed in this study was based on stability and conservation analysis, post-translational modification, secondary structure, functional interaction prediction, binding energy evaluation and finally molecular dynamic simulation. Prediction matching among the tools revealed that out of 18 SNPs, only four (rs1486407144, rs1259659354, rs1257022048 and rs1320180267) were predicted as the most damaging and highly deleterious SNPs affecting the TERF1 protein and its molecular dynamics when interacting with the TERB1 protein by influencing the function, structural stability, flexibility and compaction of the overall complex. Interestingly, these polymorphisms should be considered during genetic screening so they can be used effectively as genetic biomarkers for male infertility diagnosis.Communicated by Ramaswamy H. Sarma.

Computational study of the potential impact of AURKC missense SNPs on AURKC-INCENP interaction and their correlation to macrozoospermia.

Aurora Kinase C (AURKC) is considered an important element in Chromosome Passenger Complex (CPC), its interaction with Inner Centromere Protein (INCENP) plays a critical role in the establishment and the recruitment of a stable CPC during spermatogenesis. Genetic variations of AURKC gene are susceptible to impact AURKC-INCENP interaction, which may affect CPC stability and predispose male subjects to macrozoospermia. In this study, we systematically applied computational approaches using different bioinformatic tools to predict the effect of missense SNPs reported on AURKC gene, we selected the deleterious ones and we introduced their corresponding amino acid substitutions on AURKC protein structure. Then we did a protein-protein docking between AURKC variants and INCENP followed by a structural assessment of each resulting complex using PRODIGY server, Yassara view, Ligplot + and we choose the complexes of the most impactful variants for molecular dynamics (MD) simulation study. Seventeen missense SNPs of AURKC were identified as deleterious between all reported ones. All of them were located on relatively conserved positions on AURKC protein according to Consurf server. Only the four missense SNPs; E91K, D166V, D221Y and G235V were ranked as the most impactful ones and were chosen for MD simulation. D221Y and G235V were responsible for the most remarkable changes on AURKC-INCENP structural stability, therefore, they were selected as the most deleterious ones. Experimental studies are recommended to test the actual effect of these two variants and their actual impact on the morphology of sperm cells.Communicated by Ramaswamy H. Sarma.

Computational Analysis of the Potential Impact of MTC Complex Missenses SNPs Associated with Male Infertility.

Meiotic chromosomes endure rapid prophase movements that ease the formation of interhomologue recombination intermediates that drive synapsis, crossing over, and segregation process. To generate these fast moves, the meiotic telomere complex (MTC) enables telomere-inner nuclear membrane attachment during meiotic prophase I and transfers cytoskeletal signals via another complex: the LINC complex. Furthermore, disruption or mutations of any of the MTC genes (TERB1, TERB2, and MAJIN) alters telomere association with the nuclear envelope leading to impairment of homologous pairing and synapsis, a meiotic arrest, and consequently to male infertility. To decipher the effect of TERB1, TERB2, and MAJIN missense mutations on protein structure, stability, and function, different bioinformatic tools were used in this study including VEP, Mutabind2, Haddock, Prodigy, Ligplot, ConSurf, DUET and MusiteDeep. In total, thirty mutations were predicted to be deleterious using VEP web server: seventeen for TERB1, eleven for TERB2, and two for MAJIN. All these single nucleotide polymorphisms were further analyzed and only 11 SNPs (W8R, G25R, P649A, I624T, C618R, F607V, S604G, C592Y, C592R, G187W, and R53C) were found to be the most damaging by at least six software tools and exert deleterious effect on the TERB1, TERB2, and MAJIN protein structures and likely functions. They revealed high conservation, less stability, and having a role in posttranslational modifications. This in silico approach provides information to gain further insights about variants that might affect stability, change binding affinity, and edit protein-protein interactions to facilitate their identification and functional characterization associated with male infertility.