title: Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections.
abstract: Excessive activation of the transforming growth factor beta signaling pathway and disorganized cellular skeleton caused by genetic mutations are known to be responsible for the inherited thoracic aortic aneurysms and dissections (TAAD), a life-threatening vascular disease. To investigate the genotype-phenotype correlation, we screened genetic mutations of fibrillin-1 (FBN1), transforming growth factor-β receptor-1 (TGFBR1) and transforming growth factor-β receptor-2 (TGFBR2) for TAAD in 7 affected families and 22 sporadic patients. Of 19 potential mutations identified in FBN1, 11 appeared novel while the others were recurrent. Two mutations were detected in TGFBR2. Eight patients carried no mutation in either of these genes. Characterization of FBN1 c.5917+6T>C in transfected HEK293 cells demonstrated that it caused skipping of exon 47, leading to the loss of the 33th calcium binding epidermal growth factor-like domain associated with Marfan syndrome. Compared with exon 46, skipping of 47 did not cause patients ectopia lentis in all carriers. To correlate genotypes with phenotypes in different human ancestries, we reviewed the published mutational studies on FBN1 and found that the probability of cardiovascular defects were significantly increased in Chinese patients with premature termination codon or splicing mutations than those with missense mutations (91.7 % vs 54.2 %, P = 0.0307) or with noncysteine-involved point mutations than those with cysteine-involved mutations (88.9 % vs 33.3 %, P = 0.0131). Thus, we conclude that exon 47 skipping of FBN1 leads preferentially to cardiovascular defects and human ancestries influence genotype-phenotype correlation in TAAD.
authors: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Rd, Beijing 100871, China.
authors: Wen-Jing
authors: WJ
authors: Wang
authors: Peili
authors: P
authors: Han
authors: Jun
authors: J
authors: Zheng
authors: Fang-Yuan
authors: FY
authors: Hu
authors: Yun
authors: Y
authors: Zhu
authors: Jin-Sheng
authors: JS
authors: Xie
authors: Jian
authors: J
authors: Guo
authors: Zhe
authors: Z
authors: Zhang
authors: Jie
authors: J
authors: Dong
authors: Gu-Yan
authors: GY
authors: Zheng
authors: Huiqing
authors: H
authors: Cao
authors: Tian-Shu
authors: TS
authors: Liu
authors: Qinglin
authors: Q
authors: Fu
authors: Lizhong
authors: L
authors: Sun
authors: Bi-Bo
authors: BB
authors: Yang
authors: Xiao-Li
authors: XL
authors: Tian
mesh_terms: D000293:Adolescent; D000328:Adult; D000784:Aortic Dissection / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D001013:Aorta, Thoracic / Q000378:metabolism* / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D044466:Asian People; D002648:Child; D005091:Exons; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D015870:Gene Expression; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017434:Protein Structure, Tertiary; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D014162:Transfection; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000625841:TGFBR1 protein, human