Polymorphisms in Genes Involved in Osteoblast Differentiation and Function Are Associated with Anthropometric Phenotypes in Spanish Women

Much of the genetic variance associated with osteoporosis is still unknown. Bone mineral density (BMD) is the main predictor of osteoporosis risk, although other anthropometric phenotypes have recently gained importance. The aim of this study was to analyze the association of SNPs in genes involved in osteoblast differentiation and function with BMD, body mass index (BMI), and waist (WC) and hip (HC) circumferences. Four genes that affect osteoblast differentiation and/or function were selected from among the differentially expressed genes in fragility hip fracture (FOXC1, CTNNB1, MEF2C, and EBF2), and an association study of four single-nucleotide polymorphisms (SNPs) was conducted in a cohort of 1001 women. Possible allelic imbalance was also studied for SNP rs87939 of the CTNNB1 gene. We found significant associations of SNP rs87939 of the CTNNB1 gene with LS-sBMD, and of SNP rs1366594 of the MEF2C gene with BMI, after adjustment for confounding variables. The SNP of the MEF2C gene also showed a significant trend to association with FN-sBMD (p = 0.009). A possible allelic imbalance was ruled out as no differences for each allele were detected in CTNNB1 expression in primary osteoblasts obtained from homozygous women. In conclusion, we demonstrated that two SNPs in the MEF2C and CTNNB1 genes, both implicated in osteoblast differentiation and/or function, are associated with BMI and LS-sBMD, respectively.

Download Full-text

Identification and Functional Annotation of Genes Related to Bone Stability in Laying Hens Using Random Forests

Genes ◽

10.3390/genes12050702 ◽

2021 ◽

Vol 12 (5) ◽

pp. 702

Author(s):

Simon Jansen ◽

Ulrich Baulain ◽

Christin Habig ◽

Faisal Ramzan ◽

Jens Schauer ◽

...

Keyword(s):

Random Forests ◽

Metabolic Pathways ◽

Genetic Architecture ◽

Laying Hens ◽

Enrichment Analysis ◽

Nucleotide Polymorphisms ◽

Mineral Density ◽

Single Nucleotide ◽

Economic Problems ◽

Close Proximity

Skeletal disorders, including fractures and osteoporosis, in laying hens cause major welfare and economic problems. Although genetics have been shown to play a key role in bone integrity, little is yet known about the underlying genetic architecture of the traits. This study aimed to identify genes associated with bone breaking strength and bone mineral density of the tibiotarsus and the humerus in laying hens. Potentially informative single nucleotide polymorphisms (SNP) were identified using Random Forests classification. We then searched for genes known to be related to bone stability in close proximity to the SNPs and identified 16 potential candidates. Some of them had human orthologues. Based on our findings, we can support the assumption that multiple genes determine bone strength, with each of them having a rather small effect, as illustrated by our SNP effect estimates. Furthermore, the enrichment analysis showed that some of these candidates are involved in metabolic pathways critical for bone integrity. In conclusion, the identified candidates represent genes that may play a role in the bone integrity of chickens. Although further studies are needed to determine causality, the genes reported here are promising in terms of alleviating bone disorders in laying hens.

Download Full-text

In Silico Identification of Novel Acute Myeloid Leukemia Associated Missense SNPs in Human CEBPA Gene

Abasyn Journal Life Sciences ◽

10.34091/ajls.3.2.2 ◽

2020 ◽

pp. 10-24

Keyword(s):

Acute Myeloid Leukemia ◽

In Silico ◽

Myeloid Leukemia ◽

Gene Interaction ◽

Nucleotide Polymorphisms ◽

Future Perspectives ◽

Single Nucleotide ◽

In Silico Identification ◽

And Function ◽

Acute Myeloid

Single nucleotide polymorphisms (SNPs) in CEBPA gene have been found to be associated with cancer especially Acute Myeloid Leukemia (AML). Therefore, the identification of functional and structural polymorphisms in CEBPA is important to study and discover therapeutics targets and potential malfunctioning. For this purpose, several bioinformatics tools were used for the identification of disease-associated nsSNPs, which might be vital for the structure and function of CEBPA, making them extremely important. In silico tools used in this study included SIFT, PROVEAN, PolyPhen2, SNP&GO and PhD-SNP, followed by ConSurf and I-Mutant. Protein 3D modelling was carried out using I-TASSER and MODELLER v9.22, while GeneMANIA and string were used for the prediction of gene-gene interaction in this regard. From our study, we found that the L345P, R333C, R339Q, V328G, R327W, L317Q, N292S, E284A, R156W, Y108N and F82L mutations were the most crucial SNPs. Additionally, the gene-gene interaction showed the genes having correlation with CEBPA’s co-expressions and importance in several pathways. In future, these 11 mutations should be investigated while studying diseases related to CEBPA, especially for AML. Being the first of its kind, future perspectives are proposed in this study, which will help in precision medicine. Animal models are of great significance in finding out CEBPA effects in disease.

Download Full-text

Genes Regulating Immune Response and Amelogenesis Interact in Increasing the Susceptibility to Molar-Incisor Hypomineralization

Caries Research ◽

10.1159/000491644 ◽

2018 ◽

Vol 53 (2) ◽

pp. 217-227 ◽

Cited By ~ 10

Author(s):

Diego Girotto Bussaneli ◽

Manuel Restrepo ◽

Camila Maria Bullio Fragelli ◽

Lourdes Santos-Pinto ◽

Fabiano Jeremias ◽

...

Keyword(s):

Immune Response ◽

Gene Interactions ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Nuclear Families ◽

Molar Incisor Hypomineralization ◽

Inflammatory Stimuli ◽

Allele Specific ◽

Family Based ◽

And Function

Ameloblasts are sensitive cells whose metabolism and function may be affected by inflammatory stimuli. The aim of this study was to evaluate the possible association between polymorphisms in immune response-related genes and molar-incisor hypomineralization (MIH), and their interaction with polymorphisms in amelogenesis-related genes. DNA samples were obtained from 101 nuclear families that had at least 1 MIH-affected child. Eleven single-nucleotide polymorphisms (SNPs) were investigated in immune response genes using TaqMan® technology allele-specific probes. A transmission disequilibrium test was performed to verify overtransmission of alleles in all MIH families, as well as in families only with mild or severe MIH-affected children. Gene-gene interactions between the immune-related and amelogenesis-related polymorphisms were analyzed by determining whether alleles of those genes were transmitted from heterozygous parents more often in association than individually with MIH-affected children. In severe cases of MIH, significant results were observed for rs10733708 (TGFBR1, OR = 3.5, 95% CI = 1.1–10.6). Statistical evidence for gene-gene interactions between rs6654939 (AMELX) and the SNPs rs2070874 (IL4), rs2275913 (IL17A), rs1800872 (IL10), rs1800587 (IL1A), and rs3771300 (STAT1) was observed. The rs2070874 SNP (IL4) was also significantly overtransmitted from heterozygous parents with the rs7526319 (TUFT1) and the rs2355767 (BMP2) SNPs, suggesting a synergistic effect of the transmission of these alleles with susceptibility to MIH. This family-based study demonstrated an association between variation in TGFBR1 and MIH. Moreover, the polymorphisms in immune response and amelogenesis genes may have an additive effect on the risk of developing MIH.

Download Full-text

Timing during translation matters: synonymous mutations in human pathologies influence protein folding and function

Biochemical Society Transactions ◽

10.1042/bst20170422 ◽

2018 ◽

Vol 46 (4) ◽

pp. 937-944 ◽

Cited By ~ 10

Author(s):

Robert Rauscher ◽

Zoya Ignatova

Keyword(s):

Protein Folding ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Synonymous Mutations ◽

Translation Velocity ◽

Disease Penetrance ◽

And Function ◽

Related Proteins ◽

Translational Speed ◽

Fine Tune

Ribosomes translate mRNAs with non-uniform speed. Translation velocity patterns are a conserved feature of mRNA and have evolved to fine-tune protein folding, expression and function. Synonymous single-nucleotide polymorphisms (sSNPs) that alter programmed translational speed affect expression and function of the encoded protein. Synergistic advances in next-generation sequencing have led to the identification of sSNPs associated with disease penetrance. Here, we draw on studies with disease-related proteins to enhance our understanding of mechanistic contributions of sSNPs to functional alterations of the encoded protein. We emphasize the importance of identification of sSNPs along with disease-causing mutations to understand genotype–phenotype relationships.

Download Full-text

An update: mechanisms of microRNA in primary open-angle glaucoma

Briefings in Functional Genomics ◽

10.1093/bfgp/elaa020 ◽

2020 ◽

Author(s):

Yuanping Wang ◽

Lingzhi Niu ◽

Jing Zhao ◽

Mingxuan Wang ◽

Ke Li ◽

...

Keyword(s):

Intraocular Pressure ◽

Primary Open Angle Glaucoma ◽

Open Angle Glaucoma ◽

Nucleotide Polymorphisms ◽

Open Angle ◽

Single Nucleotide ◽

Optic Nerve Damage ◽

The World ◽

And Function ◽

Main Factor

Abstract Glaucoma is a disease with characteristic optic neuropathy and loss of vision, leading to blindness, and primary open-angle glaucoma (POAG) is the most common glaucoma type throughout the world. Genetic susceptibility is the main factor in POAG, and most susceptibility genes cause changes in microRNA expression and function, thereby leading to POAG occurrence and development. Increasing evidence indicates that many microRNAs are involved in the regulation of intraocular pressure (IOP) and play an important role in the increase in IOP in POAG. Additionally, microRNA is closely related to optic nerve damage factors (mechanical stress, hypoxia and inflammation). This review discusses the effect of single-nucleotide polymorphisms in POAG-related genes on microRNA and the value of microRNA in the diagnosis and treatment of POAG.

Download Full-text

Single nucleotide polymorphisms (SNPs) in human lactoferrin geneThis paper is one of a selection of papers published in this Special Issue, entitled 7th International Conference on Lactoferrin: Structure, Function and Applications, and has undergone the Journal's usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o06-035 ◽

2006 ◽

Vol 84 (3) ◽

pp. 381-384 ◽

Cited By ~ 15

Author(s):

Christina T. Teng ◽

Wesley Gladwell

Keyword(s):

Single Nucleotide Polymorphisms ◽

Inflammatory Responses ◽

Peer Review Process ◽

Genome Project ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Environmental Health Sciences ◽

Normal Healthy Individual ◽

Lactoferrin Gene ◽

And Function

The lactoferrin protein possesses antimicrobial and antiviral activities. It is also involved in the modulation of the immune response. In a normal healthy individual, lactoferrin plays a role in the front-line host defense against infection and in immune and inflammatory responses. Whether genomic variations, such as single nucleotide polymorphisms (SNPs), have an effect on the structure and function of lactoferrin protein and whether these variations contribute to the different susceptibility of individuals in response to environmental insults are interesting health-related issues. In this study, the lactoferrin gene was resequenced as part of the Environmental Genome Project of the National Institute of Environmental Health Sciences, which operates within the National Institutes of Health. Ninety-one healthy donors of different ethnicities were used to establish common SNPs in the exons of the lactoferrin gene in the general population. The data will serve as a basis from which study the association of lactoferrin polymorphism and disease.

Download Full-text

In Silico Analysis of Non Synonymous Single Nucleotide Polymorphisms (nsSNPs) of SMPX Gene in Hearing Impairment

10.1101/461764 ◽

2018 ◽

Cited By ~ 1

Author(s):

Md. Arifuzzaman ◽

Sarmistha Mitra ◽

Amir Hamza ◽

Raju Das ◽

Nurul Absar ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Protein Stability ◽

In Silico Analysis ◽

Normal Activity ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Binding Motifs ◽

Stability Change ◽

And Function ◽

Dbsnp Database

ABSTRACTBackgroundMutations in SMPX gene can disrupt the normal activity of the SMPX protein which is involved in hearing process.ObjectiveIn this study, deleterious non-synonymous single nucleotide polymorphisms were isolated from the neutral variants by using several bioinformatics tools.MethodFirstly, dbSNP database hosted by NCBI was used to retrieve the SNPs of SMPX gene, secondly, SIFT was used primarily to screen the damaging SNPs. Further, for validation PROVEAN, PredictSNP and PolyPhen 2 were used. I-Mutant 3 was utilized to analyze the protein stability change and MutPred predicted the molecular mechanism of protein stability change. Finally evolutionary conservation was done to study their conservancy by using ConSurf server.ResultsA total of 26 missense (0.6517%) and 3 nonsense variants (0.075%) were retrieved and among them 4 mutations were found deleterious by all the tools of this experiment and are also highly conserved according to ConSurf server. rs772775896, rs759552778, rs200892029 and rs1016314772 are the reference IDs of deleterious mutations where the substitutions are S71L, N19D, A29T and K54N. Loss of Ubiquitination, loss of methylation, loss of glycosylation, and loss of MoRF binding motifs are the root causes of protein stability change.ConclusionThis is the first study regarding nsSNPs of SMPX gene where the most damaging SNPs were screened that are associated with the SMPX gene and can be used for further research to study their effect on protein structure and function, their dynamic behavior and how they actually affect protein’s flexibility.

Download Full-text

Structural Characterization of Carbonic Anhydrase VIII and Effects of Missense Single Nucleotide Variations to Protein Structure and Function

International Journal of Molecular Sciences ◽

10.3390/ijms21082764 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2764

Author(s):

Taremekedzwa Allan Sanyanga ◽

Özlem Tastan Bishop

Keyword(s):

Carbonic Anhydrase ◽

Binding Site ◽

Cross Correlation ◽

Structure And Function ◽

The Body ◽

Conformational Sampling ◽

Nucleotide Polymorphisms ◽

Ip3 Receptor ◽

Single Nucleotide ◽

And Function

Human carbonic anhydrase 8 (CA-VIII) is an acatalytic isoform of the α -CA family. Though the protein cannot hydrate CO2, CA-VIII is essential for calcium (Ca2+) homeostasis within the body, and achieves this by allosterically inhibiting the binding of inositol 1,4,5-triphosphate (IP3) to the IP3 receptor type 1 (ITPR1) protein. However, the mechanism of interaction of CA-VIII to ITPR1 is not well understood. In addition, functional defects to CA-VIII due to non-synonymous single nucleotide polymorphisms (nsSNVs) result in Ca2+ dysregulation and the development of the phenotypes such as cerebellar ataxia, mental retardation and disequilibrium syndrome 3 (CAMRQ3). The pathogenesis of CAMRQ3 is also not well understood. The structure and function of CA-VIII was characterised, and pathogenesis of CAMRQ3 investigated. Structural and functional characterisation of CA-VIII was conducted through SiteMap and CPORT to identify potential binding site residues. The effects of four pathogenic nsSNVs, S100A, S100P, G162R and R237Q, and two benign S100L and E109D variants on CA-VIII structure and function was then investigated using molecular dynamics (MD) simulations, dynamic cross correlation (DCC) and dynamic residue network (DRN) analysis. SiteMap and CPORT analyses identified 38 unique CA-VIII residues that could potentially bind to ITPR1. MD analysis revealed less conformational sampling within the variant proteins and highlighted potential increases to variant protein rigidity. Dynamic cross correlation (DCC) showed that wild-type (WT) protein residue motion is predominately anti-correlated, with variant proteins showing no correlation to greater residue correlation. DRN revealed variant-associated increases to the accessibility of the N-terminal binding site residues, which could have implications for associations with ITPR1, and further highlighted differences to the mechanism of benign and pathogenic variants. SNV presence is associated with a reduction to the usage of Trp37 in all variants, which has implications for CA-VIII stability. The differences to variant mechanisms can be further investigated to understand pathogenesis of CAMRQ3, enhancing precision medicine-related studies into CA-VIII.

Download Full-text