Two novel splicing TBX5 mutations causing Holt-Oram syndrome.
DOI:
https://doi.org/10.14456/gag.2019.1Keywords:
TBX5; Holt-Oram syndrome; heart-hand syndrome; congenital heart disease; congenital upper limb anomaliesAbstract
Holt-Oram syndrome (HOS), deformities owing to developmental defects of heart and upper limb, is caused by the TBX5 gene encoding a transcription factor in T-box gene family. Its 1.5-kb coding sequence spans 8 exons for 518 amino acid residues. Most TBX5 mutations are located in the coding region by clustering either in the DNA-binding or in the transactivating domains of TBX5 protein, therefore we investigated 3 Thai (Mongoloid) HOS patients for their causative variants by screening of TBX5 coding sequence. Denaturing high performance liquid chromatography under partial denaturation mode was used to screen for the entire coding region before direct sequencing for specific mutation identification. We report two novel TBX5 mutations (c.983-2A>C, IVS8 as-2 A>C and c.510+5G>A, IVS5 ds+5 G>A as a de novo change) which would affect the splicing process of TBX5 transcript and another recently discovered missense mutation (c.241A>T, p.Arg81Trp) as the first report in Mongoloid HOS patients. Our findings could help extend the understanding of genotype-phenotype correlation in HOS patients which would be beneficial for clinical practice and counseling.
References
Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 76:7.20.1-7.20.41.
Al-Qattan MM, Abou Al-Shaar H (2015) Molecular basis of the clinical features of Holt-Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications. Gene 560: 129-136.
Barisic I, Boban L, Greenlees R, Garne E, Wellesley D, Calzolari E, Addor MC, Arriola L, Bergman JE, Braz P, et al. (2014) Holt Oram syndrome: a registry-based study in Europe. Orphanet J Rare Dis 9: 156.
Barnett P, Postma AV (2014) Molecular Genetics of Holt–Oram Syndrome. In: eLS. John Wiley & Sons, Ltd, Chichester, pp 1-11.
Basson CT, Cowley GS, Solomon SD, Weissman B, Poznanski AK, Traill TA, Seidman JG, Seidman CE (1994) The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med 330:885-891.
Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz S, Vaglio A, Bruzzone R, Quadrelli R, Lerone M, Romeo G, et al. (1999) Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Natl Acad Sci USA 96:2919-2924.
Bohm J, Heinritz W, Craig A, Vujic M, Ekman-Joelsson BM, Kohlhase J, Froster U (2008) Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein. BMC Med Genet 9:88.
Brassington AM, Sung SS, Toydemir RM, Le T, Roeder AD, Rutherford AE, Whitby FG, Jorde LB, Bamshad MJ (2003) Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. Am J Hum Genet 73:74-85.
Caminsky N, Mucaki EJ, Rogan PK (2014) Interpretation of mRNA splicing mutations in genetic disease: review of the literature and guidelines for information-theoretical analysis. F1000Res 3:282.
Cross SJ, Ching YH, Li QY, Armstrong-Buisseret L, Spranger S, Lyonnet S, Bonnet D, Penttinen M, Jonveaux P,
Leheup B, et al. (2000) The mutation spectrum in Holt-Oram syndrome. J Med Genet. 37:785-787.
Csaba E, Marta V, Endre C (1991) Holt–Oram syndroma. Orv Hetil 132:73–78.
De Conti L, Baralle M, Buratti E (2013) Exon and intron definition in pre-mRNA splicing. Wiley Interdiscip Rev RNA 4:49-60.
Debeer P, Race V, Gewillig M, Devriendt K, Frijns JP (2007) Novel TBX5 mutations in patients with Holt-Oram syndrome. Clin Orthop Relat Res 462:20-26.
Ersoy AO, Topcu V, Kale I, Ersoy E, Ozler S, Danisman N (2016) A novel mutated sequence in the T-box transcription factor-5 (TBX-5) gene (c.241A>T) in Holt-Oram syndrome. J Turk Ger Gynecol Assoc 17:55-57.
Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, et al. (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443-447.
Ghosh TK, Packham EA, Bonser AJ, Robinson TE, Cross SJ, Brook JD (2001) Characterization of the TBX5 binding site and analysis of mutations that cause Holt-Oram syndrome. Hum Mol Genet 10:1983-1994.
Gonzalez-Perez A, Lopez-Bigas N (2011) Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am J Hum Genet 88:440-449.
Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I (2001) Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat Genet 28:276-280.
Holt M, Oram S (1960) Familial heart disease with skeletal malformations. Br Heart J 22:236-242.
Jian X, Boerwinkle E, Liu X (2014) In silico prediction of splice-altering single nucleotide variants in the human genome. Nucleic Acids Res 42:13534-13544.
Krause A, Zacharias W, Camarata T, Linkhart B, Law E, Lischke A, Miljan E, Simon HG (2004) Tbx5 and Tbx4 transcription factors interact with a new chicken PDZ-LIM protein in limb and heart development. Dev Biol 273:106-120.
Kulisz A, Simon HG (2008) An evolutionarily conserved nuclear export signal facilitates cytoplasmic localization of the Tbx5 transcription factor. Mol Cell Biol 28:1553-1564.
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073-1081.
Lewandowski SL, Janardhan HP, Smee KM, Bachman M, Sun Z, Lazar MA, Trivedi CM (2014) Histone deacetylase 3 modulates Tbx5 activity to regulate early cardiogenesis. Hum Mol Genet 23:3801-3809.
Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, et al. (1997) Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet 15:21-29.
McDermott DA, Bressan MC, He J, Lee JS, Aftimos S, Brueckner M, Gilbert F, Graham GE, Hannibal MC, Innis JW, et al. (2005) TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatr Res 58:981-986.
McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F (2016) The Ensembl Variant Effect Predictor. Genome Biol 17:122.
Mori AD, Bruneau BG (2004) TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed. Curr Opin Cardiol 19:211-215.
Muller CW, Herrmann BG (1997) Crystallographic structure of the T domain-DNA complex of the Brachyury transcription factor. Nature 389:884-888.
Murakami M, Nakagawa M, Olson EN, Nakagawa O (2005) A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome. Proc Natl Acad Sci USA 102:18034-18039.
Newbury-Ecob RA, Leanage R, Raeburn JA, Young ID (1996) Holt-Oram syndrome: a clinical genetic study. J Med Genet 33:300-307.
Ng PC, Henikoff S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812-3814.
Poznanski AK, Gall JC Jr, Stern AM (1970) Skeletal manifestations of the Holt-Oram syndrome. Radiology 94:45-53.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. (2015) 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 17:405-424.
Schwarz JM, Rodelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7:575-576.
Smith AT, Sack GH Jr, Taylor GJ (1979) Holt-Oram syndrome. J Pediatr 95:538-543.
Soens ZT, Branch J, Wu S, Yuan Z, Li Y, Li H, Wang K, Xu M, Rajan L, Motta FL, et al. (2017) Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance. Hum Mutat 38:1521-1533.
Stirnimann CU, Ptchelkine D, Grimm C, Muller CW (2010) Structural basis of TBX5-DNA recognition: the T-box domain in its DNA-bound and -unbound form. J Mol Biol 400:71-81.
Vaughan CJ, Basson CT (2000) Molecular determinants of atrial and ventricular septal defects and patent ductus arteriosus. Am J Med Genet 97:304-309.
Will CL, Luhrmann R (2011) Spliceosome structure and function. Cold Spring Harb Perspect Biol 3:a003707.
Yeo G, Burge CB (2004) Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377-394.
Zaragoza MV, Lewis LE, Sun G, Wang E, Li L, Said-Salman I, Feucht L, Huang T (2004) Identification of the TBX5 transactivating domain and the nuclear localization signal. Gene 330:9-18.
Al-Qattan MM, Abou Al-Shaar H (2015) Molecular basis of the clinical features of Holt-Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications. Gene 560: 129-136.
Barisic I, Boban L, Greenlees R, Garne E, Wellesley D, Calzolari E, Addor MC, Arriola L, Bergman JE, Braz P, et al. (2014) Holt Oram syndrome: a registry-based study in Europe. Orphanet J Rare Dis 9: 156.
Barnett P, Postma AV (2014) Molecular Genetics of Holt–Oram Syndrome. In: eLS. John Wiley & Sons, Ltd, Chichester, pp 1-11.
Basson CT, Cowley GS, Solomon SD, Weissman B, Poznanski AK, Traill TA, Seidman JG, Seidman CE (1994) The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med 330:885-891.
Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz S, Vaglio A, Bruzzone R, Quadrelli R, Lerone M, Romeo G, et al. (1999) Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Natl Acad Sci USA 96:2919-2924.
Bohm J, Heinritz W, Craig A, Vujic M, Ekman-Joelsson BM, Kohlhase J, Froster U (2008) Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein. BMC Med Genet 9:88.
Brassington AM, Sung SS, Toydemir RM, Le T, Roeder AD, Rutherford AE, Whitby FG, Jorde LB, Bamshad MJ (2003) Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. Am J Hum Genet 73:74-85.
Caminsky N, Mucaki EJ, Rogan PK (2014) Interpretation of mRNA splicing mutations in genetic disease: review of the literature and guidelines for information-theoretical analysis. F1000Res 3:282.
Cross SJ, Ching YH, Li QY, Armstrong-Buisseret L, Spranger S, Lyonnet S, Bonnet D, Penttinen M, Jonveaux P,
Leheup B, et al. (2000) The mutation spectrum in Holt-Oram syndrome. J Med Genet. 37:785-787.
Csaba E, Marta V, Endre C (1991) Holt–Oram syndroma. Orv Hetil 132:73–78.
De Conti L, Baralle M, Buratti E (2013) Exon and intron definition in pre-mRNA splicing. Wiley Interdiscip Rev RNA 4:49-60.
Debeer P, Race V, Gewillig M, Devriendt K, Frijns JP (2007) Novel TBX5 mutations in patients with Holt-Oram syndrome. Clin Orthop Relat Res 462:20-26.
Ersoy AO, Topcu V, Kale I, Ersoy E, Ozler S, Danisman N (2016) A novel mutated sequence in the T-box transcription factor-5 (TBX-5) gene (c.241A>T) in Holt-Oram syndrome. J Turk Ger Gynecol Assoc 17:55-57.
Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, et al. (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443-447.
Ghosh TK, Packham EA, Bonser AJ, Robinson TE, Cross SJ, Brook JD (2001) Characterization of the TBX5 binding site and analysis of mutations that cause Holt-Oram syndrome. Hum Mol Genet 10:1983-1994.
Gonzalez-Perez A, Lopez-Bigas N (2011) Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am J Hum Genet 88:440-449.
Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I (2001) Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat Genet 28:276-280.
Holt M, Oram S (1960) Familial heart disease with skeletal malformations. Br Heart J 22:236-242.
Jian X, Boerwinkle E, Liu X (2014) In silico prediction of splice-altering single nucleotide variants in the human genome. Nucleic Acids Res 42:13534-13544.
Krause A, Zacharias W, Camarata T, Linkhart B, Law E, Lischke A, Miljan E, Simon HG (2004) Tbx5 and Tbx4 transcription factors interact with a new chicken PDZ-LIM protein in limb and heart development. Dev Biol 273:106-120.
Kulisz A, Simon HG (2008) An evolutionarily conserved nuclear export signal facilitates cytoplasmic localization of the Tbx5 transcription factor. Mol Cell Biol 28:1553-1564.
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073-1081.
Lewandowski SL, Janardhan HP, Smee KM, Bachman M, Sun Z, Lazar MA, Trivedi CM (2014) Histone deacetylase 3 modulates Tbx5 activity to regulate early cardiogenesis. Hum Mol Genet 23:3801-3809.
Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, et al. (1997) Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet 15:21-29.
McDermott DA, Bressan MC, He J, Lee JS, Aftimos S, Brueckner M, Gilbert F, Graham GE, Hannibal MC, Innis JW, et al. (2005) TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatr Res 58:981-986.
McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F (2016) The Ensembl Variant Effect Predictor. Genome Biol 17:122.
Mori AD, Bruneau BG (2004) TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed. Curr Opin Cardiol 19:211-215.
Muller CW, Herrmann BG (1997) Crystallographic structure of the T domain-DNA complex of the Brachyury transcription factor. Nature 389:884-888.
Murakami M, Nakagawa M, Olson EN, Nakagawa O (2005) A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome. Proc Natl Acad Sci USA 102:18034-18039.
Newbury-Ecob RA, Leanage R, Raeburn JA, Young ID (1996) Holt-Oram syndrome: a clinical genetic study. J Med Genet 33:300-307.
Ng PC, Henikoff S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812-3814.
Poznanski AK, Gall JC Jr, Stern AM (1970) Skeletal manifestations of the Holt-Oram syndrome. Radiology 94:45-53.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. (2015) 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 17:405-424.
Schwarz JM, Rodelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7:575-576.
Smith AT, Sack GH Jr, Taylor GJ (1979) Holt-Oram syndrome. J Pediatr 95:538-543.
Soens ZT, Branch J, Wu S, Yuan Z, Li Y, Li H, Wang K, Xu M, Rajan L, Motta FL, et al. (2017) Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance. Hum Mutat 38:1521-1533.
Stirnimann CU, Ptchelkine D, Grimm C, Muller CW (2010) Structural basis of TBX5-DNA recognition: the T-box domain in its DNA-bound and -unbound form. J Mol Biol 400:71-81.
Vaughan CJ, Basson CT (2000) Molecular determinants of atrial and ventricular septal defects and patent ductus arteriosus. Am J Med Genet 97:304-309.
Will CL, Luhrmann R (2011) Spliceosome structure and function. Cold Spring Harb Perspect Biol 3:a003707.
Yeo G, Burge CB (2004) Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377-394.
Zaragoza MV, Lewis LE, Sun G, Wang E, Li L, Said-Salman I, Feucht L, Huang T (2004) Identification of the TBX5 transactivating domain and the nuclear localization signal. Gene 330:9-18.
Downloads
Published
2019-04-30
Issue
Section
Research Articles
