TGFBR3 variation is not a common cause of Marfan-like syndrome and Loeys-Dietz-like syndrome

Journal of Negative Results in Biomedicine

Mine Arslan-Kirchner¹  Britta Keyser¹  Joerg Schmidtke¹  Krishna K Singh² 

[1] Institute of Human Genetics, Hannover Medical School, Hannover, Germany;Division of Cardiac Surgery, St. Michael's Hospital, Toronto, Canada

关键词: variants;    TGFBR3;    LDS;    MFS;   

Others  :  820518
DOI  :  10.1186/1477-5751-11-9

 received in 2011-09-15, accepted in 2012-02-02,  发布年份 2012

【 摘 要 】

Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 (FBN1) gene, and mutations in FBN1 are known to be responsible for over 90% of all MFS cases. Locus heterogeneity has also been reported and confirmed, with mutations in the receptor genes TGFBR1 and TGFBR2 identified in association with MFS-related phenotypes. It is now known that dysregulation of TGF-ß signaling is involved in MFS pathogenesis. To test the hypothesis that dysregulation of TGFBR3-associated TGF-ß signaling is implicated in MFS or related phenotype pathogenesis, we selected a cohort of 49 patients, fulfilling or nearly fulfilling the diagnostic criteria for MFS. The patients were known not to carry a mutation in the FBN1 gene (including three 5' upstream alternatively spliced exons), the TGFBR1 and TGFBR2 genes. Mutation screening for the TGFBR3 gene in these patients and in controls led to the identification of a total of ten exonic (one novel), four intronic (one novel) and one 3'UTR variant in the TGFBR3 gene. Our data suggest that variations in TGFBR3 gene appear not to be associated with MFS or related phenotype.

【 授权许可】

   
2012 Singh et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Collod G, Babron MC, Jondeau G, Coulon M, Weissenbach J, Dubourg O, Bourdarias JP, Bonaiti-Pellie C, Junien C, Boileau C: A second locus for Marfan syndrome maps to chromosome 3p24.2-p25. Nat Genet 1994, 8(3):264-268.
• [2]Mizuguchi T, Collod-Beroud G, Akiyama T, Abifadel M, Harada N, Morisaki T, Allard D, Varret M, Claustres M, Morisaki H, et al.: Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 2004, 36(8):855-860.
• [3]Singh KK, Rommel K, Mishra A, Karck M, Haverich A, Schmidtke J, Arslan-Kirchner M: TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat 2006, 27(8):770-777.
• [4]Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, et al.: A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005, 37(3):275-281.
• [5]Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, et al.: Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006, 355(8):788-798.
• [6]Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, Sakai LY, Dietz HC: Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003, 33(3):407-411.
• [7]Byers PH: Determination of the molecular basis of Marfan syndrome: a growth industry. J Clin Invest 2004, 114(2):161-163.
• [8]Pepin MC, Beauchemin M, Collins C, Plamondon J, O'Connor-McCourt MD: Mutagenesis analysis of the membrane-proximal ligand binding site of the TGF-beta receptor type III extracellular domain. FEBS Lett 1995, 377(3):368-372.
• [9]Cheifetz S, Bassols A, Stanley K, Ohta M, Greenberger J, Massague J: Heterodimeric transforming growth factor beta. Biological properties and interaction with three types of cell surface receptors. J Biol Chem 1988, 263(22):10783-10789.
• [10]Lopez-Casillas F, Wrana JL, Massague J: Betaglycan presents ligand to the TGF beta signaling receptor. Cell 1993, 73(7):1435-1444.
• [11]De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE: Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996, 62(4):417-426.
• [12]Rommel K, Karck M, Haverich A, von Kodolitsch Y, Rybczynski M, Muller G, Singh KK, Schmidtke J, Arslan-Kirchner M: Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome. Hum Mutat 2005, 26(6):529-539.
• [13]Rommel K, Karck M, Haverich A, Schmidtke J, Arslan-Kirchner M: Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with Marfan syndrome or Marfanoid features leads to the identification of 11 novel and three previously reported mutations. Hum Mutat 2002, 20(5):406-407.
• [14]Singh KK, Shukla PC, Rommel K, Schmidtke J, Arslan-Kirchner M: Sequence variations in the 5' upstream regions of the FBN1 gene associated with Marfan syndrome. Eur J Hum Genet 2006, 14(7):876-879.