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http://dx.doi.org/10.5808/gi.21070

Presentation of potential genes and deleterious variants associated with non-syndromic hearing loss: a computational approach  

Ray, Manisha (Department of Pathology and Lab Medicine, All India Institute of Medical Sciences)
Rath, Surya Narayan (Department of Bioinformatics, Odisha University of Agriculture and Technology)
Sarkar, Saurav (Department of Ear Nose Throat, All India Institute of Medical Sciences)
Sable, Mukund Namdev (Department of Pathology and Lab Medicine, All India Institute of Medical Sciences)
Publication Information
Genomics & Informatics / v.20, no.1, 2022 , pp. 5.1-5.10 More about this Journal
Abstract
Non-syndromic hearing loss (NSHL) is a common hereditary disorder. Both clinical and genetic heterogeneity has created many obstacles to understanding the causes of NSHL. The present study has attempted to ravel the genetic aetiology in NSHL progression and to screen out potential target genes using computational approaches. The reported NSHL target genes (2009-2020) have been studied by analyzing different biochemical and signaling pathways, interpretation of their functional association network, and discovery of important regulatory interactions with three previously established miRNAs in the human inner ear as well as in NSHL such as miR-183, miR-182, and miR-96. This study has identified SMAD4 and SNAI2 as the most putative target genes of NSHL. But pathogenic and deleterious non-synonymous single nucleotide polymorphisms discovered within SMAD4 is anticipated to have an impact on NSHL progression. Additionally, the identified deleterious variants in the functional domains of SMAD4 added a supportive clue for further study. Thus, the identified deleterious variant i.e., rs377767367 (G491V) in SMAD4 needs further clinical validation. The present outcomes would provide insights into the genetics of NSHL progression.
Keywords
computational approach; functional association network; miRNAs; non-syndromic hearing loss; single nucleotide polymorphism;
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1 Kiernan AE. Notch signaling during cell fate determination in the inner ear. Semin Cell Dev Biol 2013;24:470-479.   DOI
2 Munnamalai V, Fekete DM. Wnt signaling during cochlear development. Semin Cell Dev Biol 2013;24:480-489.   DOI
3 Zhou J, Zhang C, Zhou B, Jiang D. miR-183 modulated cell proliferation and apoptosis in ovarian cancer through the TGF-beta/ Smad4 signaling pathway. Int J Mol Med 2019;43:1734-1746.
4 Aretz S, Stienen D, Uhlhaas S, Stolte M, Entius MM, Loff S, et al. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet 2007;44:702-709.   DOI
5 Fan R, Dong L, Li P, Wang X, Chen X. Integrated bioinformatics analysis and screening of hub genes in papillary thyroid carcinoma. PLoS One 2021;16:e0251962.   DOI
6 Kuang C, Chen Y. Tumor-derived C-terminal mutations of Smad4 with decreased DNA binding activity and enhanced intramolecular interaction. Oncogene 2004;23:1021-1029.   DOI
7 Bitarafan F, Seyedena SY, Mahmoudi M, Garshasbi M. Identification of novel variants in Iranian consanguineous pedigrees with nonsyndromic hearing loss by next-generation sequencing. J Clin Lab Anal 2020;34:e23544.   DOI
8 Cunningham LL, Tucci DL. Hearing loss in adults. N Engl J Med 2017;377:2465-2473.   DOI
9 Schrijver I. Hereditary non-syndromic sensorineural hearing loss: transforming silence to sound. J Mol Diagn 2004;6:275-284.   DOI
10 Karimizadeh E, Sharifi-Zarchi A, Nikaein H, Salehi S, Salamatian B, Elmi N, et al. Analysis of gene expression profiles and protein-protein interaction networks in multiple tissues of systemic sclerosis. BMC Med Genomics 2019;12:199.   DOI
11 Srivastava N, Mishra BN, Srivastava P. Protein network analysis to prioritize key genes and pathway for stress-mediated neurodegeneration. Open Bioinformatics J 2018;11:240-251.   DOI
12 Thomson DW, Bracken CP, Goodall GJ. Experimental strategies for microRNA target identification. Nucleic Acids Res 2011;39:6845-6853.   DOI
13 Chadly DM, Best J, Ran C, Bruska M, Wozniak W, Kempisty B, et al. Developmental profiling of microRNAs in the human embryonic inner ear. PLoS One 2018;13:e0191452.   DOI
14 Bush WS, Moore JH. Chapter 11: Genome-wide association studies. PLoS Comput Biol 2012;8:e1002822.   DOI
15 Bozanic Urbancic N, Battelino S, Tesovnik T, Trebusak Podkrajsek K. The importance of early genetic diagnostics of hearing loss in children. Medicina (Kaunas) 2020;56:471.   DOI
16 Cabanillas R, Dineiro M, Cifuentes GA, Castillo D, Pruneda PC, Alvarez R, et al. Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients. BMC Med Genomics 2018;11:58.   DOI
17 Shaffer JR, Feingold E, Marazita ML. Genome-wide association studies: prospects and challenges for oral health. J Dent Res 2012;91:637-641.   DOI
18 Schenone M, Dancik V, Wagner BK, Clemons PA. Target identification and mechanism of action in chemical biology and drug discovery. Nat Chem Biol 2013;9:232-240.   DOI
19 Rai A, Shinde P, Jalan S. Network spectra for drug-target identification in complex diseases: new guns against old foes. Appl Netw Sci 2018;3:51.   DOI
20 Zhu HM, Fei Q, Qian LX, Liu BL, He X, Yin L. Identification of key pathways and genes in nasopharyngeal carcinoma using bioinformatics analysis. Oncol Lett 2019;17:4683-4694.
21 Chen L, Chu C, Lu J, Kong X, Huang T, Cai YD. Gene ontology and KEGG pathway enrichment analysis of a drug target-based classification system. PLoS One 2015;10:e0126492.   DOI
22 Das SS, Chakravorty N. Identification of deleterious SNPs and their effects on BCL11A, the master regulator of fetal hemoglobin expression. Genomics 2020;112:397-403.   DOI
23 Tomkins JE, Manzoni C. Advances in protein-protein interaction network analysis for Parkinson's disease. Neurobiol Dis 2021;155:105395.   DOI
24 Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res 2012;40:W452-W457.   DOI
25 Zhao HB, Kikuchi T, Ngezahayo A, White TW. Gap junctions and cochlear homeostasis. J Membr Biol 2006;209:177-186.   DOI
26 Solda G, Robusto M, Primignani P, Castorina P, Benzoni E, Cesarani A, et al. A novel mutation within the MIR96 gene causes non-syndromic inherited hearing loss in an Italian family by altering pre-miRNA processing. Hum Mol Genet 2012;21:577-585.   DOI
27 Hildebrand MS, Witmer PD, Xu S, Newton SS, Kahrizi K, Najmabadi H, et al. miRNA mutations are not a common cause of deafness. Am J Med Genet A 2010;152:646-652.
28 Matsuda K. PCR-based detection methods for single-nucleotide polymorphism or mutation: real-time PCR and its substantial contribution toward technological refinement. Adv Clin Chem 2017;80:45-72.   DOI
29 Shastry BS. SNPs in disease gene mapping, medicinal drug development and evolution. J Hum Genet 2007;52:871-880.   DOI
30 Bendl J, Stourac J, Salanda O, Pavelka A, Wieben ED, Zendulka J, et al. PredictSNP: robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Comput Biol 2014;10:e1003440.   DOI
31 Bendl J, Musil M, Stourac J, Zendulka J, Damborsky J, Brezovsky J. PredictSNP2: a unified platform for accurately evaluating SNP effects by exploiting the different characteristics of variants in distinct genomic regions. PLoS Comput Biol 2016;12:e1004962.   DOI
32 Riccomagno MM, Takada S, Epstein DJ. Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh. Genes Dev 2005;19:1612-1623.   DOI
33 Wang B, Hu B, Yang S. Cell junction proteins within the cochlea: a review of recent research. J Otol 2015;10:131-135.   DOI
34 Hirata H, Ueno K, Shahryari V, Tanaka Y, Tabatabai ZL, Hinoda Y, et al. Oncogenic miRNA-182-5p targets Smad4 and RECK in human bladder cancer. PLoS One 2012;7:e51056.   DOI
35 Sindura KP, Banerjee M. An immunological perspective to non-syndromic sensorineural hearing loss. Front Immunol 2019;10:2848.   DOI
36 Udhaya Kumar S, Thirumal Kumar D, Bithia R, Sankar S, Magesh R, Sidenna M, et al. Analysis of differentially expressed genes and molecular pathways in familial hypercholesterolemia involved in atherosclerosis: a systematic and bioinformatics approach. Front Genet 2020;11:734.   DOI
37 Kitajiri S, Katsuno T. Tricellular tight junctions in the inner ear. Biomed Res Int 2016;2016:6137541.   DOI
38 Wilson T, Omelchenko I, Foster S, Zhang Y, Shi X, Nuttall AL. JAK2/STAT3 inhibition attenuates noise-induced hearing loss. PLoS One 2014;9:e108276.   DOI
39 Mittal R, Liu G, Polineni SP, Bencie N, Yan D, Liu XZ. Role of microRNAs in inner ear development and hearing loss. Gene 2019;686:49-55.   DOI
40 Sohmer H. Pathophysiological mechanisms of hearing loss. J Basic Clin Physiol Pharmacol 1997;8:113-125.   DOI
41 Lewis MA, Di Domenico F, Ingham NJ, Prosser HM, Steel KP. Hearing impairment due to Mir183/96/182 mutations suggests both loss and gain of function effects. Dis Model Mech 2020;14:dmm047225.
42 Gallione C, Aylsworth AS, Beis J, Berk T, Bernhardt B, Clark RD, et al. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet A 2010;152A:333-339.   DOI
43 Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004;363:852-859.   DOI
44 Howe JR, Sayed MG, Ahmed AF, Ringold J, Larsen-Haidle J, Merg A, et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet 2004;41:484-491.   DOI
45 Alazzouzi H, Alhopuro P, Salovaara R, Sammalkorpi H, Jarvinen H, Mecklin JP, et al. SMAD4 as a prognostic marker in colorectal cancer. Clin Cancer Res 2005;11:2606-2611.   DOI
46 Attisano L, Lee-Hoeflich ST. The Smads. Genome Biol 2001;2:REVIEWS3010.
47 Nayak G, Lee SI, Yousaf R, Edelmann SE, Trincot C, Van Itallie CM, et al. Tricellulin deficiency affects tight junction architecture and cochlear hair cells. J Clin Invest 2013;123:4036-4049.   DOI
48 Trune DR. Ion homeostasis in the ear: mechanisms, maladies, and management. Curr Opin Otolaryngol Head Neck Surg 2010;18:413-419.   DOI
49 Du X, Li Q, Yang L, Liu L, Cao Q, Li Q. SMAD4 activates Wnt signaling pathway to inhibit granulosa cell apoptosis. Cell Death Dis 2020;11:373.   DOI
50 Ueno K, Hirata H, Shahryari V, Deng G, Tanaka Y, Tabatabai ZL, et al. microRNA-183 is an oncogene targeting Dkk-3 and SMAD4 in prostate cancer. Br J Cancer 2013;108:1659-1667.   DOI
51 Mahmoodian Sani MR, Hashemzadeh-Chaleshtori M, Saidijam M, Jami MS, Ghasemi-Dehkordi P. MicroRNA-183 family in inner ear: hair cell development and deafness. J Audiol Otol 2016;20:131-138.   DOI
52 Yuan Y, You Y, Huang D, Cui J, Wang Y, Wang Q, et al. Comprehensive molecular etiology analysis of nonsyndromic hearing impairment from typical areas in China. J Transl Med 2009;7:79.   DOI
53 Korver AM, Smith RJ, Van Camp G, Schleiss MR, Bitner-Glindzicz MA, Lustig LR, et al. Congenital hearing loss. Nat Rev Dis Primers 2017;3:16094.   DOI