TMCO1 Gen Sekans Varyanlatlarının Fonksiyonel Özelliklerinin In Silico Analizlerlerle Değerlendirilmesi

Yıl 2019, Cilt: 7 Sayı: 3, 1931 - 1946, 31.07.2019

Dilek Pirim Erva Ulusoy Zeynep Kurt Niyazi Kaya Elif Uz-yıldırım

https://doi.org/10.29130/dubited.571528

Öz

Transmembran and Coiled-Coil Domains 1 (TMCO1) proteini, TMCO1 geni tarafından kodlanır ve 7
ekzondan oluşur. Önceki çalışmalar serebrofasiotorasik displazili (SFTD)
hastalarda çok sayıda TMCO1 varyantı
tanımlamış ve TMCO1 lokusunun primer
açık açılı glokom hastalığı ile (PAAG) ilişkili olduğunu göstermiştir. Bununla
birlikte TMCO1 gen sekansı
varyantlarının ilişkilerini bildiren sınırlı sayıda araştırma vardır ve elde
edilen bulguların çoğu anlamsız mutasyonlar ve çerçeve kayması mutasyonlarının TMCO1 varyantlarının patojenliğini ve
klinik fenotiplerle ilişkilerini belirtmektedir. Bu nedenle, TMCO1'de aminoasit
değişikliklerine neden olan tek nükleotid varyantlarının fonksiyonel
özellikleri henüz tam olarak açıklanamamıştır. Bu çalışmada aminoasit
değişikliklerinin protein yapısı üzerindeki etkilerini, post-translasyon
modifikasyonlardaki (PTM) ve TMCO1 proteini için düzenleyici mekanizmadaki
olası rollerini belirledik. Yaygın olarak kullanılan in silico araçları  (SIFT, MutationTaster2, Polyphen2) ile
yaptığımız analizin değerlendirmesine göre 41 adet yanlış anlamlı mutasyon
barındıran varyantı patojenik olarak sınıflandırdık. Bu 41 varyanttan dördü
(p.K211Q, p.K105E, p.S235F, p.K237R) PTM ve düzenleyici protein bağlama
bölgelerinde yer almaktadır, bu nedenle bu varyantların fonksiyon üzerinde
etkili olduğunu düşündük. Bununla birlikte, rs1387528611 (s.Lys128Gln)
varyantının (RegulomeDB skoru= 2b) düzenleyici varyant olabileceğine dair güçlü
biyolojik kanıtlar olduğunu saptadık. In silico analizlerimizin sonuçları, TMCO1 ile ilişkili hastalık
fenotiplerine katkıda bulunabilecek yanlış anlamlı TMCO1 varyantların fonksiyonel önemini ve insan hastalıklarındaki
rollerini ortaya çıkarmak için in vivo değerlendirmenin işlevsel önemini
vurgulamaktadır.

Anahtar Kelimeler

TMCO1, Serebrofasiyotorasik displazi, RegulomeDB, SNV, Post-translasyonel modifikasyonlar, in silico analiz

Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses

Öz

Transmembrane
and Coiled-Coil Domains 1 (TMCO1) protein is encoded by TMCO1 gene consists of 7 exons. Previous studies have identified
multiple TMCO1 variants in patients
with cerebro-facio-thoracic dysplasia (CFTD) and TMCO1 locus was also shown to be associated with primary open angle
glaucoma (POAG). However, there are limited number of research exist reporting
associations of the TMCO1 gene
sequence variants and majority of the findings affirm the pathogenicity of the
nonsense and frameshift TMCO1 variants
and their associations with clinical phenotypes. Thus functional properties of
the single nucleotide variants causing amino acid changes in the TMCO1 are yet
to be comprehensively elucidated. In this study, we evaluated the effects of
amino acid substitutions on protein structure, identified their putative roles
in post-translational modifications (PTM) and in regulatory mechanism for TMCO1
protein. We classified 41 missense variants as pathogenic based on combined
scores of common in silico tools (SIFT, MutationTaster2, Polyphen2). Of these
41 variants, four (p.K211Q, p.K105E, p.S235F, p.K237R) were identified to be
located in PTMs and regulatory protein binding sites; thus they were proposed
to be putative functional variants. Moreover, rs1387528611 (p.Lys128Gln) had
also strong evidence (RegulomeDB score=2b) for its possible regulatory
function. The results of our in silico analyses highlight the functional
importance of the missense TMCO1
variants that may contribute to the TMCO1-associated
disease phenotypes and further in vivo evaluation yet to be needed to uncover
their role in human diseases.

Anahtar Kelimeler

TMCO1, Cerebro-facio-thoracic dysplasia, RegulomeDB, SNV, post-translational modifications, in silico analyses

Kaynakça

• [1] Z. Zhang, D. Mo, P. Cong, Z. He, F. Ling, A. Li, Y. Niu, X. Zhao, C. Zhou, Y. Chen, “Molecular cloning, expression patterns and subcellular localization of porcine TMCO1 gene,” Molec Biol Rep, vol. 37, no. 3, pp. 1611-1618, 2010.
• [2] S. Iwamuro, M. Saeki, S. Kato, “Multi-ubiquitination of a nascent membrane protein produced in a rabbit reticulocyte lysate,” J Biochem, vol. 126, no. 1, pp. 48-53, 1999.
• [3] B. Xin, E. G. Puffenberger, S. Turben, H. Tan, A. Zhou, H. Wang, “Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation,” Proc Natl Acad Sci U S A, vol. 107, no. 1, pp. 258-263, 2010.
• [4] A. O. Caglayan, H. Per, G. Akgumus, H. Gumus, J. Baranoski, M. Canpolat, M. Calik, A. Yikilmaz, K. Bilguvar, S. Kumandas, M. Gunel, “Whole-exome sequencing identified a patient with TMCO1 defect syndrome and expands the phenotic spectrum,” Clin Genet, vol. 84, no. 4, pp. 394-395, 2013.
• [5] Y. Alanay, B. Ergüner, E. Utine, O. Haçariz, P. O. Kiper, E. Z. Taşkıran, F. Perçin, E. Uz, M. Ş. Sağiroğlu, B. Yuksel, K. Boduroglu, N. A. Akarsu, “TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia,” Am J Med Genet A, vol. 164A, no. 2, pp. 291-304, 2014.
• [6] J. A. F. Tender, C. R. Ferreira, “Cerebro-facio-thoracic dysplasia (Pascual-Castroviejo syndrome): Identification of a novel mutation, use of facial recognition analysis, and review of the literature,” Transl Sci Rare Dis, vol. 3, no. 1, pp. 37-43, 2018.
• [7] T. Michael Yates, O. H. Ng, A. C. Offiah, J. Willoughby, J. N. Berg, D. D. D. Study, D. S. Johnson, “Cerebrofaciothoracic dysplasia: Four new patients with a recurrent TMCO1 pathogenic variant,” Am J Med Genet A, vol. 179, no. 1, pp. 43-49, 2019.
• [8] D. Pehlivan, E. Karaca, H. Aydin, C. R. Beck, T. Gambin, D. M. Muzny, B. Bilge Geckinli, A. Karaman, S. N. Jhangiani, R. A. Gibbs, J. R. Lupski, “Whole-exome sequencing links TMCO1 defect syndrome with cerebro-facio-thoracic dysplasia,” Eur J Hum Genet, vol. 22, no. 9, pp. 1145-1148, 2014.
• [9] K. P. Burdon, S. Macgregor, A. W. Hewitt, S. Sharma, G. Chidlow, R. A. Mills, P. Danoy, R. Casson, A. C. Viswanathan, J. Z. Liu, J. Landers, A. K. Henders, J. Wood, E. Souzeau, A. Crawford, P. Leo, J. J. Wang, E. Rochtchina, D. R. Nyholt, N. G. Martin, G. W. Montgomery, P. Mitchell, M. A. Brown, D. A. Mackey, J. E. Craig, “Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1,” Nat Genet, vol. 43, no. 6, pp. 574-578, 2011.
• [10] S. Sharma, K. P. Burdon, G. Chidlow, S. Klebe, A. Crawford, D. P. Dimasi, A. Dave, S. Martin, S. Javadiyan, J. P. Wood, R. Casson, P. Danoy, K. Griggs, A. W. Hewitt, J. Landers, P. Mitchell, D. A. Mackey, J. E. Craig, “Association of genetic variants in the TMCO1 gene with clinical parameters related to glaucoma and characterization of the protein in the eye,” Invest Ophthalmol Vis Sci, vol. 53, no. 8, pp. 4917-4925, 2012.
• [11] Micheal S, Ayub H, Khan MI, Bakker B, Schoenmaker-Koller FE, Ali M, Akhtar F, Khan WA, Qamar R, den Hollander AI, “Association of known common genetic variants with primary open angle, primary angle closure, and pseudoexfoliation glaucoma in Pakistani cohorts,” Mol Vis, vol. 4, no. 20, pp. 1471-1479, 2014.
• [12] A. B. Ozel, S. E. Moroi, D. M. Reed, M. Nika, C. M. Schmidt, S. Akbari and P. R. Lichter, ”Genome-wide association study and meta-analysis of intraocular pressure,” Human genetics, vol.133, no.1, pp.41-57, 2014.
• [13] T. E. Scheetz, B. Faga, L. Ortega, B. R. Roos, M. O. Gordon, M. A. Kass, K. Wang, J. H. Fingert, “Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study,” Ophthalmology, vol. 123, no. 12, pp. 2527-2536, 2016.
• [14] L. Verkuil, I. Danford, M. Pistilli, D. W. Collins, H. V. Gudiseva, B. T. Trachtman, J. He, S. Rathi, N. Haider, G. S. Ying, V. R. M. Chavali, J. M. O'Brien, “SNP located in an AluJb repeat downstream of TMCO1, rs4657473, is protective for POAG in African Americans.” Br J Ophthalmol, doi: 10.1136/bjophthalmol-2018-313086, 2019
• [15] Y. Liu, M. A. Hauser, S. K. Akafo, X. Qin, S. Miura, J. R. Gibson, J. Wheeler, D. E. Gaasterland, P. Challa, L. W. Herndon, International Consortium of African Ancestry REsearch in Glaucoma, R. Ritch, S. E. Moroi, L. R. Pasquale, C. A. Girkin, D. L. Budenz, J. L. Wiggs, J. E. Richards, A. E. Ashley-Koch, R. R. Allingham, “Investigation of known genetic risk factors for primary open angle glaucoma in two populations of African ancestry, ”Invest Ophthalmol Vis Sci, vol. 54, no. 9, pp. 6248-6254, 2013.
• [16] Y. Chen, C. Qiu, S. Qian, J. Chen, X. Chen, L. Wang, X. Sun, “Lack of Association of rs1192415 in TGFBR3-CDC7 With Visual Field Progression: A Cohort Study in Chinese Open Angle Glaucoma Patients,” Front Genet, vol. 24, no. 9, pp. 488-495, 2018.
• [17] L. M. van Koolwijk, W. D. Ramdas, M. K. Ikram, N. M. Jansonius, F. Pasutto, P. G. Hysi, S. Macgregor, S. F. Janssen, A. W. Hewitt, A. C. Viswanathan, J. B. ten Brink, S. M. Hosseini, N. Amin, D. D. Despriet, J. J. Willemse-Assink, R. Kramer, F. Rivadeneira, M. Struchalin, Y. S. Aulchenko, N. Weisschuh, M. Zenkel, C. Y. Mardin, E. Gramer, U. Welge-Lüssen, G. W. Montgomery, F. Carbonaro, T. L. Young, DCCT/EDIC Research Group, C. Bellenguez, P. McGuffin, P. J. Foster, F. Topouzis, P. Mitchell, J. J. Wang, T. Y. Wong, M. A. Czudowska, A. Hofman, A. G. Uitterlinden, R. C. Wolfs, P. T. de Jong, B. A. Oostra, A. D. Paterson, Wellcome Trust Case Control Consortium 2, D. A. Mackey, A. A. Bergen, A. Reis, C. J. Hammond, J. R. Vingerling, H. G. Lemij, C. C. Klaver, C. M. van Duijn, “Common genetic determinants of intraocular pressure and primary open-angle glaucoma,” PLoS Genet, vol. 8, no. 5, pp. e1002611, 2012. [18] A. A. Kondkar, A. Mousa, T. A. Azad, T. Sultan, A. Alawad, S. Altuwaijri, S. A. Al-Obeidan, K. K. Abu-Amero, “Polymorphism rs7555523 in transmembrane and coiled-coil domain 1 (TMCO1) is not a risk factor for primary open angle glaucoma in a Saudi cohort,” J Negat Results Biomed, vol. 15, no. 1, pp. 17, 2016.
• [19] Q. C. Wang, Q. Zheng, H. Tan, B. Zhang, X. Li, Y. Yang, J. Yu, Y. Liu, H. Chai, X. Wang, Z. Sun, J. Q. Wang, S. Zhu, F. Wang, M. Yang, C. Guo, H. Wang, Q. Zheng, Y. Li, Q. Chen, A. Zhou, T. S. Tang, “TMCO1 Is an ER Ca(2+) Load-Activated Ca(2+) Channel,” Cell, vol. 165, no. 6, pp. 1454-1466, 2016.
• [20] Z. Sun, H. Zhang, X. Wang, Q. C. Wang, C. Zhang, J. Q. Wang, Y. H. Wang, C. Q. An, K. Y. Yang, Y. Wang, F. Gao, C. Guo, T. S. Tang, “TMCO1 is essential for ovarian follicle development by regulating ER Ca(2+) store of granulosa cells,” Cell Death Differ, vol. 25, no. 9, pp. 1686-1701, 2018.
• [21] D. Cilliers, Y. Alanay, K. Boduroglu, E. Utine, E. Tunçbilek, J. Clayton-Smith, “Cerebro-facio-thoracic dysplasia: expanding the phenotype,” Clin Dysmorphol, vol. 16, no. 2, pp. 121-125, 2007.
• [22] J. N. Bailey, S. J. Loomis, J. H. Kang, R. R. Allingham, P. Gharahkhani, C. C. Khor, K. P. Burdon, H. Aschard, D. I. Chasman, R. P. Jr. Igo, P. G. Hysi, C. A. Glastonbury, A. Ashley-Koch, M. Brilliant, A. A. Brown, D. L. Budenz, A. Buil, C. Y. Cheng, H. Choi, W. G. Christen, G. Curhan, I. De Vivo, J. H. Fingert, P. J. Foster, C. Fuchs, D. Gaasterland, T. Gaasterland, A. W. Hewitt, F. Hu, D. J. Hunter, A. P. Khawaja, R. K. Lee, Z. Li, P. R. Lichter, D. A. Mackey, P. McGuffin, P. Mitchell, S. E. Moroi, S. A. Perera, K. W. Pepper, Q. Qi, T. Realini, J. E. Richards, P. M. Ridker, E. Rimm, R. Ritch, M. Ritchie, J. S. Schuman, W. K. Scott, K. Singh, A. J. Sit, Y. E. Song, R. M. Tamimi, F. Topouzis, A. C. Viswanathan, S. S. Verma, D. Vollrath, J. J. Wang, N. Weisschuh, B. Wissinger, G. Wollstein, T. Y. Wong, B. L. Yaspan, D. J. Zack, K. Zhang, Study EN, ANZRAG Consortium, R. N. Weinreb, M. A. Pericak-Vance, K. Small, C. J. Hammond, T. Aung, Y. Liu, E. N. Vithana, S. MacGregor, J. E. Craig, P. Kraft, G. Howell, M. A. Hauser, L. R. Pasquale, J. L. Haines, J. L. Wiggs, “Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma,” Nat Genet, vol. 48, no. 2, pp. 189-194, 2016
• [23] H. Duzkale, J. Shen, H. McLaughlin, A. Alfares, M. A. Kelly, T. J. Pugh, B. H. Funke, H. L. Rehm, M. S. Lebo, “A systematic approach to assessing the clinical significance of genetic variants,” Clin Genet, vol. 84, no. 5, pp. 453-463, 2013.
• [24] Q. Li, K. Wang, “InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines,” Am J Hum Genet, vol. 100, no. 2, pp. 267-280, 2017.
• [25] P. Kumar, S. Henikoff, P. C. Ng, “Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm,” Nat Protoc, vol. 4, no. 7, pp. 1073-1081, 2009.
• [26] I. A. Adzhubei, S. Schmidt, L. Peshkin, V. E. Ramensky, A. Gerasimova, P. Bork, A. S. Kondrashov, S. R. Sunyaev, “A method and server for predicting damaging missense mutations,” Nat Methods, vol. 7, no. 4, pp. 248-249, 2010.
• [27] J. M. Schwarz, C. Rödelsperger, M. Schuelke, D. Seelow, “MutationTaster evaluates disease-causing potential of sequence alterations,” Nat Methods, vol. 7, no. 8, pp. 575-576, 2010. [28] A. P. Boyle, E. L. Hong, M. Hariharan, Y. Cheng, M. A. Schaub, M. Kasowski, K. J. Karczewski, J. Park, B. C. Hitz, S. Weng, J. M. Cherry, M. Snyder, “Annotation of functional variation in personal genomes using RegulomeDB,” Genome Research, vol. 22, no. 9, pp. 1790-1797, 2012. [29] P. V. Hornbeck, B. Zhang, B. Murray, J. M. Kornhauser, V. Latham, E. Skrzypek, “PhosphoSitePlus, 2014: mutations, PTMs and recalibrations,” Nucleic Acids Res, vol. 43, pp. 512-520, 2015.
• [30] Y. Arinaminpathy, E. Khurana, D. M. Engelman, M. B. Gerstein, “Computational analysis of membrane proteins: the largest class of drug targets,” Drug Discov Today, vol.14, no. 23-24, pp.1130-1135, 2009.
• [31] M. S. Cline, R. Karchin, “Using bioinformatics to predict the functional impact of SNVs,” Bioinformatics, vol. 27, no. 4, pp. 441-448, 2011.
• [32] H. Tang, P. D. Thomas, “Tools for Predicting the Functional Impact of Nonsynonymous Genetic Variation,” Genetics, vol. 203, no. 2, pp. 635-647, 2016.
• [33] S. Richards, N. Aziz, S. Bale, D. Bick, S. Das, J. Gastier-Foster, W. W. Grody, M. Hegde, E. Lyon, E. Spector, K. Voelkerding, H. L. Rehm, “ ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology,” Genet Med, vol. 17, no. 5, pp. 405-424, 2015.
• [34] R. Ghosh, N. Oak, S. E. Plon, “Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines,” Genome Biol, vol. 18, no. 1, pp. 225, 2017.
• [35] J. Thusberg, A. Olatubosun, M. Vihinen M, “Performance of mutation pathogenicity prediction methods on missense variants,” Hum Mutat, vol. 32, no. 4, pp. 358-368, 2011.
• [36] K. Frousios, C. S. Iliopoulos, T. Schlitt, M. A. Simpson, “ Predicting the functional consequences of non-synonymous DNA sequence variants--evaluation of bioinformatics tools and development of a consensus strategy,” Genomics, vol. 102, no. 4, pp. 223-228, 2013.
• [37] S. Narayan, G. D. Bader, J. Reimand, “Frequent mutations in acetylation and ubiquitination sites suggest novel driver mechanisms of cancer,” Genome Med, vol. 8, no. 1, pp. 55, 2016.
• [38] A. B. Stergachis, E. Haugen, A. Shafer, W. Fu, B. Vernot, A. Reynolds, A. Raubitschek, S. Ziegler, E. M. LeProust, J. M. Akey, J. A. Stamatoyannopoulos, “Exonic transcription factor binding directs codon choice and affects protein evolution,” Science, vol. 342, no. 6164, pp. 1367-72, 2013.
• [39] V. K. Yadav, K. S. Smith, C. Flinders, S. M. Mumenthaler, S. De, “Significance of duon mutations in cancer genomes,” Sci Rep, vol. 8, no. 6, pp. 27437, 2016.
• [40] B. A. B. Stergachis, E. Haugen, A. Shafer, W. Fu, B. Vernot, A. Reynolds, A. Raubitschek, S. Ziegler, E. M. LeProust, J. M. Akey, and J. A. Stamatoyannopoulos, “Exonic Transcription Factor Binding Directs Codon Choice and Affects Protein Evolution,” Science, vol. 342, no. 6164, pp. 1325-1326, 2013.