Computational Modeling of complete HOXB13 protein for predicting the functional effect of SNPs and the associated role in hereditary prostate cancer

Abstract

The human HOXB13 gene encodes a 284 amino acid transcription factor belonging to the homeobox gene family containing a homeobox and a HoxA13 N-terminal domain. It is highly linked to hereditary prostate cancer, the majority of which is manifested as a result of a Single Nucleotide Polymorphism (SNP). In silico analysis of 95 missense SNP’s corresponding to the non-homeobox region of HOXB13 predicted 21 nsSNP’s to be potentially deleterious. Among 123 UTR SNPs analysed by UTRScan, rs543028086, rs550968159, rs563065128 were found to affect the UNR_BS, GY-BOX and MBE UTR signals, respectively. Subsequent analysis by PolymiRTS revealed 23 UTR SNPs altering the miRNA binding site. The complete HOXB13_M26 protein structure was modelled using MODELLER v9.17. Computational analysis of the 21 nsSNP’s mapped into the HOXB13_M26 protein revealed seven nsSNP’s (rs761914407, rs8556, rs138213197, rs772962401, rs778843798, rs770620686 and rs587780165) seriously resulting in a damaging and deleterious effect on the protein. G84E, G135E, and A128V resulted in increased, while, R215C, C66R, Y80C and S122R resulted in decreased protein stability, ultimately predicted to result in the altered binding patterns of HOXB13. While the genotype-phenotype based effects of nsSNP’s were assessed, the exact biological and biochemical mechanism driven by the above predicted SNPs still needs to be extensively evaluated by in vivo and GWAS studies.

Mutation HOXB13 c.853delT in Martinican prostate cancer patients

“…Recently, an in silico analysis suggested that the deleterious HOXB13 variants increase the stability of the HOXB13 protein, overexpressing the genes responsible for cell proliferation and growth as RFX6. 16 Among the inclusion criteria was ancestry, thus all subjects were of Martinican descent. The Martinican population consists mainly of African people (>90%) with some interbreeding with French Caucasian.…”

“…Furthermore, the knockdown of HOXB13 would inhibit cell proliferation of ovarian tumors. Recently, an in silico analysis suggested that the deleterious HOXB13 variants increase the stability of the HOXB13 protein, overexpressing the genes responsible for cell proliferation and growth as RFX6 16 . A previous study by Huang et al 17 demonstrated that the RFX6 variant (rs339331) might influence the expression of RFX6 by increasing binding of HOXB13 to transcriptional enhancer.…”

Androgen receptor enhancer usage and the chromatin regulatory landscape in human prostate cancers

“…Whether the G84E mutation affects the HOXB13-AR interactions remains elusive. From computational analyses, it is predicted that the mutation results in damaging and deleterious effects on HOXB13 DNA-binding capacity and increased stability of its protein structure (Chandrasekaran et al 2017). While hereditary HOXB13 mutations have been extensively reported in tissue, it remains to be determined whether this mutation affects HOXB13 and/or AR chromatin binding in vitro.…”

In silico analysis of a novel causative mutation in Cadherin23 gene identified in an Omani family with hearing loss

“…The mutation frequency spectrum of CDH23 among the recessive inherited cases is 5.7% in the Japanese population and 15% in the Korean population [16,19,49]. Other gene variants were also analyzed using such programs such as V66 M variant of human BDNF in psychiatric disorders and computational modeling of complete HOXB13 protein for predicting the functional effect of SNPs and the associated role in hereditary prostate cancer [50,51]. The American College of Medical Genetics and Genomics (ACMG) guide for the interpretation of sequence variants elaborated the usefulness of the predictive software programs for risk estimation and accurate interpretation of the potential causality of sequence variation [52].…”