Prediction of the functional consequences of a novel homozygous TBX5 variant in isolated AVSD patient
DOI:
https://doi.org/10.56511/JIPBS.2017.v4.i03.pp97-105Abstract
Objectives: The T-box transcription factor TBX5 gene is an important factor in mammalian cardiac development for both cardiac septation and morphogenesis. Autosomal dominant variants in the human TBX5 gene cause the known Holt-Oram syndrome (HOS); a disorder characterized by heart and upper limb deformities. Because there are rare studies for detection of TBX5 variants in isolated congenital cardiac septal defects, the current study aimed to identify the putative function of novel detected TBX5 gene variant in non-HOS patient with congenital cardiac septal defects (CSD). Methods: This is a case study of a one year old female congenital heart disease (CHD) patient with atrioventricular septal defect (AVSD). Using Direct Sanger sequencing, screening of T-box DNA binding domain corresponding exons for the patient who had normal Nkx2-5 and GATA4 genotyping was performed, as well as, a group of twenty eight non-cardiac children were screened as controls. Results: A novel homozygous missense (p.L135R) variant in the N- terminal of the T- box domain was detected with a predictive disease causing effect. This variant was absent in the variants registration databases and in 28 healthy controls, indicating its possible role in causing (CHD). Conclusions: To our knowledge, we show for the first time homozygous TBX5 variant in non-HOS associated cardiac malformations in an Egyptian patient. Absence of definite congenital heart defects symptoms in the unaffected carrier parents for the p.L135R variant supporting dosage-sensitivity hypothesis and a probable new mode of Tbx5 variants inheritance
Keywords:
Isolated cardiac septal defects, TBX5 gene, Novel homozygous variantDownloads
References
Holt M, and Oram S: Familial heart disease with skeletal malformations. Br Heart J. 1960; 22: 236-242.
Cross J, Ching H, Li L, Armstrong-Buisseret L, Spranger S, Munnich A, Bonnet D, Pentinnen M, Jonveaux P, Mortier G, Van Ravenswaaij C and Gardiner CA: The mutation spectrum in Holt-Oram syndrome. J Med Genet. 2000; 37:785-787.
McDermott D, Bressan M, He J, Lee JS, Aftimos S, Brueckner M, Gilbert F, Graham GE, Hannibal MC, Innis JW, Pierpont ME, Raas-Rothschild A, Shanske AL, Smith WE, Spencer RH, St John-Sutton MG, van Maldergem L, Waggoner DJ, Weber M and Basson CT: TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatr Res. 2005; 58:981 – 986.
Lichiardopol C, Militaru C, Popescu B, Hila G and Mixich F: Holt-Oram syndrome. Rom. J. Morphol. Embryol. 2007; 48:67 – 70.
Postma A, van de Meerakker J, Mathijssen I, Barnett P, Christoffels V, Ilgun A, Lam J, Wilde A, Deprez R and Moorman A: A Gain-of-Function TBX5 Mutation Is Associated With Atypical Holt – Oram Syndrome and Paroxysmal Atrial Fibrillation. Circ Res. 2008; 102:1433-1442.
Baban A, Pitto L, Pulignani S, Cresci M, Mariani L, Gambacciani C, Digilio MC, Pongiglione G and Albanese S: Holt-Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation: functional characterization of a de novo TBX5 mutation. Am J Med Genet A. 2014;164A:1419 – 1424
Guo D, Li R, Yuan F, Shi H, Hou X, Qu X, Xu Y, Zhang M, Liu X, Jiang J, Yang Y and Qiu X: TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome. Molecular Medicine Reports. 2016; 13:4349-4356. doi.org/10.3892/mmr.2016.5043
Ma J, Yang F, Mahida S, Zhao L, Chen X, Zhang M, Sun Z, Yao Y, Zhang Y, Zheng G, Dong J, Feng MJ, Zhang R, Sun J, Li S, Wang QS, Cao H, Benjamin EJ, Ellinor PT, Li YG and Tian XL: TBX5 mutations contribute to earlyonset atrial fibrillation in Chinese and Caucasians. Cardiovasc. Res. 2016; 109:442 – 450.
Zhang X., Qiu X., Yuan, F., Wang J., Zhao C., Li R., et al. TBX5 loss-offunction mutation contributes to familial dilated cardiomyopathy. Biochem Biophys Res Commun. 2015; 459:166 – 171.
Basson C, Bachinsky D, Lin R, Levi T, Elkins J, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG and Seidman CE: Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet. 1997; 15:30-35.
Li Q, Newbury-Ecob R, Terrett J, Wilson D, Curtis A, Yi C, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ and Brook JD: Holt-Oram syndrome is caused by mutations in TBX5 a member of the Brachyury T gene family. Nat Genet. 1997; 15: 21-29.
Greulich F, Rudat C and Kispert A: Mechanisms of T-box gene function in the developing heart. Cardiovasc Res. 2011; 91:212 – 22.
Basson C, Huang T, Lin R, Bachinsky D, Weremowicz S, Vaglio A, Bruzzone R, Quadrelli R, Lerone M, Romeo G, Silengo M, Pereira A, Krieger J, Mesquita SF, Kamisago M, Morton CC, Pierpont ME, Müller CW, Seidman JG and Seidman CE: Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Natl Acad Sci USA. 1999; 96:2919 – 2924.
Brassington A, Sung S, Toydemir R, Le T, Roeder A, Rutherford A, Whitby FG, Jorde LB and Bamshad MJ: Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. Am J Hum Genet. 2003; 73:74-85.
Dreßen M, Lahm H, Lahm A, Wolf K, Doppler S, Deutsch MA, Cleuziou J, Pabst von Ohain J, Schön P, Ewert P, Malcic I, Lange R and Krane M: A novel de novo TBX5 mutation in a patient with Holt – Oram syndrome leading to a dramatically reduced biological function. Mol Genet Genomic Med . 2016; 5:557 – 567. doi: 10.1002/mgg3.234
Ghalli I, Salah N, Hussien F, Erfan M, El-Ruby M and Mazen I: Egyptian growth curves for infants, children and adolescents. In: Satorio A., Buckler J.M.H., Marazzi N., editors. Crecere nel mondo. Ferring Publisher; Italy: 2008.
Goldmuntz E, Geiger E and Benson D: NKX2.5 mutations in patients with tetralogy of Fallot. Circulation 2001; 104:2565-2568.
Okubo A, Miyoshi O, Baba K, Takagi M, Tsukamoto K, Kinoshita A, Yoshiura K, Kishino T, Ohta T, Niikawa N and Matsumoto N: A novel GATA4 mutation completely segregated with atrial septal defect in a large Japanese family. J Med Genet. 2004; 41: 97.
http://eng.intronbio.com . Accessed 23 Sept 2015.
http://dna.macrogen.com. Accessed 11 Nov 2015.
https://www.ncbi.nlm.nih.gov/clinvar/variation/375289. Accessed 1 Jun 2016.
https://www.ncbi.nlm.nih.gov/snp/1057519050 . Accessed 1 Jun 2016.
https://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=12&fro m=114836484&to=114836484>s=rs1057519050&mk=114836484:114 836484|rs1057519050 . Accessed 1 Jun 2016.
Heracle BioSoft (2013): DNA Baser Sequence Assembler v4.7.0., http://www.DnaBaser.com. Accessed 1 Dec 2015.
Schwarz J., Cooper D., Schuelke M., Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014; 11: 361-362.
http://snp-nexus.org Accessed 3 Dec 2015.
Flicek M, Amode R, Barrell D, Beal K, Billis K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fitzgerald S, Gil L, García Girón C, Gordon L, Hourlier T, Hunt S, Johnson N, Juettemann T, Kähäri A, Keenan S, Kulesha E, Martin F, Maurel T, McLaren W, Murphy D, Nag R, Overduin B, Pignatelli M, Pritchard B, Pritchard E, Riat H, Ruffier M, Sheppard D, Taylor K, Thormann A, Trevanion S, Vullo A, Wilder S, Wilson M, Zadissa A, Aken B, Birney E, Cunningham F, Harrow J, Herrero J, Hubbard T, Kinsella R, Muffato M, Parker A, Spudich G, Yates A, Zerbino D and Searle S: Ensembl 2014. Nucleic Acids Res 2014; 42: 749-755.
Kelley L, Mezulis S , Yates C , Wass M and Sternberg M : The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 2015; 10:845-858.
http://www.expasy.org/spdbv . Accessed 12 Dec 2015.
Zuker's RNA folding algorithm. http://www.bioinfo.rpi. edu/~zukerm/seqanal. Accessed 12 Dec 2015.
http://www.fruitfly.org/seq_tools/splice.html . Accessed 12 Dec 2015.
Huang H, Chien C, Jen K and Huang H: RegRNA: an integrated web server for identifying regulatory RNA motifs and elements. Nucleic Acids Research. 2006; 34:W429 – W434. doi: 10.1093/nar/gkl333.
http://predictor.nchu.edu.tw/ istable. Accessed 5 Jun 2017.
Verma R and Babu A: Human chromosomes: manual of basic Tissue culture techniques and chromosome preparation. New York: Pergamon Press. 1989; 44-52.
ISCN 2009: an international System for human cytogenetic nomenclature (2009). In: Shaffer LG, Slovak ML, Campbell LJ, Eds. Basel: S. Karger, 2009.
https://www.ncbi.nlm.nih.gov/nuccore/31652233 . Accessed 24 Nov 2015.
Moskowitz I, Pizard A, Patel V, Bruneau B, Kim J, Kupershmidt S, Roden D, Berul C, Seidman C and Seidman J: The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system. Development 2004; 131:4107-4116.
Eker H , Altunoglu U , Toksoy G and Kayserili H : Holt-Oram syndrome because of the novel TBX5 mutation c.481A>C. Clin Dysmorphol. 2016; 4:192-194. doi: 10.1097/MCD.0000000000000121.
Stirnimann C, Ptchelkine D, Grimm C and Muller C: Structural basis of TBX5-DNA recognition: theT-boxdomaininitsDNA-boundand-unbound form. J Mol Biol. 2010; 400:71 – 81.
Debeer P, Race V, Gewillig M, Devriendt K and Frijns J: Novel TBX5 mutations in patients with Holt-Oram syndrome. Clin Orthop Relat Res. 2007; 4:20 – 26.
Heinritz W, Shou L, Moschik A and Froster U: The human TBX5 gene mutation database. Hum Mutat 2005; 26:397.
Smemo S, Campos L, Moskowitz I, Krieger J, Pereira A and Nobrega M: Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Human Molecular Genetics 2012; 21:3255 – 3263.
Al-Qattan M and Abou Al-Shaar H: A novel missense mutation in the TBX5 gene in a Saudi infant with Holt-Oram syndrome. Saudi Med. J. 2015; 36:980-982.
Takeuchi J, Koshiba-Takeuchi K, Suzuki T, Kamimura M, Ogura K and Ogura T: Tbx5 and Tbx4 trigger limb initiation through activation of the Wnt/Fgf signaling cascade. Development 2003; 130:2729 – 2739.
Mori A, Zhu Y, Vahora I, Nieman B, Koshiba-Takeuchi K, Davidson L, Pizard A, Seidman JG, Seidman CE, Chen XJ, Henkelman RM and Bruneau BG: Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis. Dev. Biol., 2006; 297:566 – 586.
Albalat R, Baquero M and Minguillon C: Identification and characterisation of the developmental expression pattern of tbx5b, a novel tbx5 gene in zebrafish. Gene. Expr. Patterns. 2010; 10:24– 30.
Darwich R , Li W , Yamak A , Komati H , Andelfinger G , Sun K and Nemer M: KLF13 is a genetic modifier of the Holt-Oram syndrome gene TBX5. Hum Mol Genet. 2017; 26:942-954. doi: 10.1093/hmg/ddx009.
Reamon-Buettner S and Borlak J: TBX5 Mutations in Non-Holt-Oram Syndrome (HOS) Malformed Hearts. Hum Mutat. 2004; 24:104.
Published
How to Cite
Issue
Section
Copyright (c) 2017 Alaaeldin. G. Fayez, Nora N. Esmaiel, Arwa A. El Darsh, Engy A. Ashaat, Alaa K. Kamel, Ghada M. Shehata, Azza M. Ahmed, Mona O. El Ruby
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Journal of Innovations in Pharmaceutical and Biological Sciences is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Based on a work at