FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited

被引:70
作者
Ades, LC
Sullivan, K
Biggin, A
Haan, EA
Brett, M
Holman, KJ
Dixon, J
Robertson, S
Holmes, AD
Rogers, J
Bennetts, B
机构
[1] Childrens Hosp, Dept Clin Genet, Westmead, NSW 2145, Australia
[2] Childrens Hosp, Marfan Res Grp, Westmead, NSW 2145, Australia
[3] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia
[4] Childrens Hosp, Dept Mol Genet, Westmead, NSW 2145, Australia
[5] Victoria Univ Wellington, Cent Reg Genet Serv, Wellington, New Zealand
[6] Univ Otago, Dept Paediat & Child Hlth, Otago, New Caledonia
[7] Royal Childrens Hosp, Melbourne Craniofacial Unit, Melbourne, Vic, Australia
关键词
Marfan syndrome; marfanoid-craniosynostosis/retardation syndromes; FBN1; TGF-beta signaling pathway disorder;
D O I
10.1002/ajmg.a.31202
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The recent identification of TGFBR2 mutations in Marfan syndrome II (MFSII) [Mizuguchi et al. (2004); Nat Genet 36:855-860] and of TGFBR1 and TGFBR2 mutations ill Loeys-Dietz aortic aneurysm syndrome (LDS) [Loeys et al. (2005); Nat Genet 37:275-281] [OMIM 609192] has provided direct evidence of abnormal signaling in transforming growth factors beta (TGF-beta) in the pathogenesis of Marfan syndrome (MFS). In light of this, we describe the phenotypes and genotypes of five individuals. Patient 1 had MFS and abnormal cranial dura. Patient 2 had severe early onset MFS and an abnormal skull. Patients 3 and 41 had probable Furlong syndrome (FS). Patient 5 had marfanoid (MD) features, Menial retardation (MR), and a deletion of chromosome 15q21.1q21.3. All patients had a condition within the MFS, MD-craniosynostosis (CS) or MD-MR spectrum. The names of these entities may become redundant, and instead, come to he considered within the spectrum of TGF-beta signaling pathway disorders. Two recurrent heterozygous FBN1 imitations were found in Patients I and 2, and an identical novel heterozygous de novo TGFBR1 mutation was found in Patients 3 and 4, in whom altered fibrillin-1 processing was demonstrated previously [Milewicz et al. (2000); Am J Hum Genet 67:279]. A heterozygous FBN1 deletion was found in Patient 5. These findings support the notion that perturbation of extracellular matrix homeostasis and/or remodeling caused by abormal TGF-beta signaling is the core pathogenetic mechanism in MFS and related entities including the MD-CS syndromes. (c) 2006 Wiley-Liss, Inc.
引用
收藏
页码:1047 / 1058
页数:12
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