Dataset Information

Computational Analysis of High Risk Missense Variant in Human UTY Gene: A Candidate Gene of AZFa Sub-region.

ABSTRACT: BACKGROUND:The human Ubiquitously transcribed tetratricopeptide repeat gene, Y-linked (UTY) gene encodes histone demethylase involved in protein-protein interactions. UTY protein evidence at protein level predicted intracellular and secreted protein. UTY is also involved in spermatogenesis process. METHODS:The high-risk non-synonymous single nucleotide polymorphism in the coding region of the UTY gene was screened by SNP database and identified missense variants were subjected to computational analysis to understand the effect on protein function, stability and structure by SIFT, PolyPhen 2, PANTHER, PROVEAN, I-Mutant 2, iPTREE-STAB, ConSurf, ModPred, SPARKS-X, QMEAN, PROCHECK, project HOPE and STRING. RESULTS:A total of 151 nsSNPs variants were retrieved in UTY gene out of which one missense variant (E18D) was predicted to be damaging or deleterious using SIFT, PolyPhen 2, PANTHER and PROVEAN. Additionally, E18D variant showed less stability, high conservation and having role in post translation modification using i-Mutant 2 and iPTREE-STAB, ConSurf and ModPred, respectively. The predicted 3D model of UTY using SPARKS-X with z-score of 15.16 was generated and validated via QMEAN (Z-score of 0.472) and PROCHECK which plots Ramachandran plot (85.3% residues in most favored regions, 12.3% in additionally allowed regions, 2.0% in generously allowed regions and 4.0% were in disallowed regions) and it indicates a good quality model. STRING showed that UTY interacts with ten different proteins. CONCLUSION:This study revealed that SNP data available on database was deduced to find out the most damaging nsSNPs i.e. rs3212293 (E18D). Therefore, it provides useful information about functional SNPs for future prospects concerning infertility in men.

SUBMITTER: Nailwal M

PROVIDER: S-EPMC5641439 | biostudies-literature | 2017 Jul-Sep

REPOSITORIES: biostudies-literature

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Computational Analysis of High Risk Missense Variant in Human UTY Gene: A Candidate Gene of AZFa Sub-region.

Nailwal Mili M Chauhan Jenabhai Bhathibhai JB

Journal of reproduction & infertility 20170701 3

<h4>Background</h4>The human Ubiquitously transcribed tetratricopeptide repeat gene, Y-linked (UTY) gene encodes histone demethylase involved in protein-protein interactions. UTY protein evidence at protein level predicted intracellular and secreted protein. UTY is also involved in spermatogenesis process.<h4>Methods</h4>The high-risk non-synonymous single nucleotide polymorphism in the coding region of the UTY gene was screened by SNP database and identified missense variants were subjected to ...[more]

PMID: 29062794

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Project description:The Ubiquitous Transcribed Y (UTY a.k.a. KDM6C) AZFa candidate gene on the human Y chromosome and its paralog on the X chromosome, UTX (a.k.a. KDM6A), encode a histone lysine demethylase removing chromatin H3K27 methylation marks at genes transcriptional start sites for activation. Both proteins harbour the conserved Jumonji C (JmjC) domain, functional in chromatin metabolism, and an extended N-terminal tetratricopeptide repeat (TPR) block involved in specific protein interactions. Specific antisera for human UTY and UTX proteins were developed to distinguish the expression of both proteins in human germ cells by immunohistochemical experiments on appropriate tissue sections. In the male germ line, UTY was expressed in the fraction of A spermatogonia located at the basal membrane, probably including spermatogonia stem cells. UTX expression was more spread in all spermatogonia and in early spermatids. In female germ line, UTX expression was found in the primordial germ cells of the ovary. UTY was also expressed during fetal male germ cell development, whereas UTX expression was visible only at distinct gestation weeks. Based on these results and the conserved neighboured location of UTY and DDX3Y in Yq11 found in mammals of distinct lineages, we conclude that UTY, such as DDX3Y, is part of the Azoospermia factor a (AZFa) locus functioning in human spermatogonia to support the balance of their proliferation-differentiation rate before meiosis. Comparable UTY and DDX3Y expression was also found in gonadoblastoma and dysgerminoma cells found in germ cell nests of the dysgenetic gonads of individuals with disorders of sexual development and a Y chromosome in karyotype (DSD-XY). This confirms that AZFa overlaps with GBY, the Gonadoblastoma susceptibility Y locus, and includes the UTY gene.Lay summaryAZFa Y genes are involved in human male germ cells development and support gonadoblastoma (germ cell tumour precursor cells) in the aberrant germ cells of the gonads of females with genetic disorders of sexual development. The AZFa UTY gene on the male Y chromosome is equivalent to UTX on the female X chromosome. These genes are involved in removing gene regulators to enable activation of other genes (i.e. removal of histone methylation known as epigenetic modifications). We wanted to learn the function of UTY and UTX in developing sperm and eggs in human tissues and developed specific antibodies to detect both proteins made by these genes. Both UTY and UTX proteins were detected in adult and fetal sperm precursor cells (spermatogonia). UTX was detected in egg precursor cells (primordial germ cells). UTY was detected in gonadoblastoma and dysgerminoma tumour cells (germ cell tumours originating from genetic disorders of sexual development due to having a Y chromosome). Based on our study, we conclude that UTY is not only part of AZFa, but also of GBY the overlapping gonadoblastoma susceptibility Y region.

Project description:BackgroundFamilial ovarian cancer (OC) cases not harbouring pathogenic variants in either of the BRCA1 and BRCA2 OC-predisposing genes, which function in homologous recombination (HR) of DNA, could involve pathogenic variants in other DNA repair pathway genes.MethodsWhole exome sequencing was used to identify rare variants in HR genes in a BRCA1 and BRCA2 pathogenic variant negative OC family of French Canadian (FC) ancestry, a population exhibiting genetic drift. OC cases and cancer-free individuals from FC and non-FC populations were investigated for carrier frequency of FANCI c.1813C>T; p.L605F, the top-ranking candidate. Gene and protein expression were investigated in cancer cell lines and tissue microarrays, respectively.ResultsIn FC subjects, c.1813C>T was more common in familial (7.1%, 3/42) than sporadic (1.6%, 7/439) OC cases (P = 0.048). Carriers were detected in 2.5% (74/2950) of cancer-free females though female/male carriers were more likely to have a first-degree relative with OC (121/5249, 2.3%; Spearman correlation = 0.037; P = 0.011), suggesting a role in risk. Many of the cancer-free females had host factors known to reduce risk to OC which could influence cancer risk in this population. There was an increased carrier frequency of FANCI c.1813C>T in BRCA1 and BRCA2 pathogenic variant negative OC families, when including the discovery family, compared to cancer-free females (3/23, 13%; OR = 5.8; 95%CI = 1.7-19; P = 0.005). In non-FC subjects, 10 candidate FANCI variants were identified in 4.1% (21/516) of Australian OC cases negative for pathogenic variants in BRCA1 and BRCA2, including 10 carriers of FANCI c.1813C>T. Candidate variants were significantly more common in familial OC than in sporadic OC (P = 0.04). Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the Fanconi anaemia (FA) pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level, destabilized by DNA damaging agent treatment in both HeLa and OC cell lines, and exhibited sensitivity to cisplatin but not to a poly (ADP-ribose) polymerase inhibitor. By tissue microarray analyses, FANCI protein was consistently expressed in fallopian tube epithelial cells and only expressed at low-to-moderate levels in 88% (83/94) of OC samples.ConclusionsThis is the first study to describe candidate OC variants in FANCI, a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that pathogenic FANCI variants may modify OC risk in cancer families.

Project description:BACKGROUND:Osteodysplasia of the oral and maxillofacial bone is generally accompanied by systemic bone abnormalities (such as short stature, joint contracture) or other systemic abnormalities (such as renal, dermatological, cardiovascular, optic, or hearing disorders). However, it does not always present this way. Recent reports have suggested that genome-wide sequencing is an effective method for identifying rare or new disorders. Here, we performed whole-exome sequencing (WES) in a patient with a unique form of acquired, local osteodysplasia of the oral and maxillofacial region. CASE PRESENTATION:A 46-year-old woman presented to our hospital with the complaint of gradually moving mandibular teeth (for 6?months), changing facial appearance, and acquired osteolysis of the oral and maxillofacial bones, showing mandibular hypoplasia without family history. Upon skeletal examination, there were no abnormal findings outside of the oral and maxillofacial area; the patient had a height of 157?cm and bone mineral density (according to dual energy x-ray absorptiometry) of 90%. Results of blood and urine tests, including evaluation of bone metabolism markers and neurological and cardiovascular examinations, were normal. We performed WES of genomic DNA extracted from the blood of this patient and her mother, who did not have the disease, as a negative control. We identified 83 new missense variants in the patient, not detected in her mother, including a candidate single nucleotide variant in exon 14 of PCNT (pericentrin). Critical homozygous or compound heterozygous variants in PCNT are a known cause of microcephalic osteodysplastic primordial dwarfism type II accompanied by mandibular hypoplasia, which is similar to the maxillofacial phenotype in this patient. CONCLUSIONS:Protein simulations performed using Polymorphism Phenotyping v2 and Combined Annotation Dependent Depletion software indicated that this missense variant is likely to disrupt the PCNT protein structure. These results suggest that this is a new form of osteolysis related to this PCNT variant.

Project description:Traditional cancer treatment approaches are often hindered by the presence of toxic side effects and the high rate of relapse observed in treated organs. In contrast, novel immunotherapeutic strategies targeting immune checkpoint inhibitors, particularly PD-1, have demonstrated promising results with minimal adverse effects. However, the emergence of immunotherapeutic-resistant tumors, predominantly caused by intrinsic mutations, poses a significant obstacle to successful treatment outcomes. Consequently, the primary objective of this study was to screen for the most detrimental missense mutations in the PD-1 gene associated with immunotherapeutic resistance. To achieve this aim, a comprehensive screening process utilizing 20 web servers, incorporating both sequence- and structure-based methodologies, was undertaken. Through meticulous analysis and mutual disease association sorting, four specific missense mutations were successfully identified. These mutations, namely, R38C, D61V, R94C, and D117V, emerged as the leading contributors to genetic cancer progression and immunotherapeutic resistance against PD-1 blockers. The findings presented in this study are supported by multiple lines of evidence. A thorough examination of protein topology, structural alignment, docking interactions with PD-L1, and protein flexibility collectively confirmed the pathogenic nature of these sorted mutations. By considering these various aspects, we have gained a comprehensive understanding of the underlying mechanisms driving immunotherapeutic resistance. In conclusion, the comprehensive screening process undertaken in this study has successfully identified R38C, D61V, R94C, and D117V as the primary mutations contributing to genetic cancer progression and immunotherapeutic resistance against PD-1 blockers. The integration of protein topology analysis, structural alignment, docking studies with PD-L1, and assessment of protein flexibility have collectively provided robust evidence to support the pathogenic significance of these mutations.

Dataset Information

Computational Analysis of High Risk Missense Variant in Human UTY Gene: A Candidate Gene of AZFa Sub-region.

Publications

Computational Analysis of High Risk Missense Variant in Human UTY Gene: A Candidate Gene of AZFa Sub-region.

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