Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype–phenotype correlations in FBN1 exons 24–40

Tiecke, Frank; Katzke, Stefanie; Booms, Patrick; Robinson, Peter N.; Neumann, Luitgard M.; Godfrey, Maurice; Mathews, Kurt R.; Scheuner, Maren T.; Hinkel, G. K.; Brenner, Rolf E.; Hövels-Gürich, Hedwig H.; Hagemeier, Christian; Fuchs, Josefine; Skovby, Flemming; Rosenberg, Thomas

doi:10.1038/sj.ejhg.5200582

Cited by 149 publications

(110 citation statements)

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“…Changes in TB domain residues could indirectly affect the binding of Ca 2ϩ by adjacent cbEGF domains through the formation of altered interdomain interfaces. A number of these mutations in domains TB3 and TB4 are currently under investigation, including G1013R (13,34), T1020A (35), and K1023N (36) in the TB3 linker and E1605K (37) in the TB4 linker. The I1048T substitution in cbEGF11, which has previously been shown to introduce an additional glycosylation site (38), may also function by disrupting the packing of TB3 to cbEGF11, because Ile-1048 is part of the conserved XG interdomain packing site (Fig.…”

Section: Ca 2ϩ -Dependent Interface Formation In Fibrillin-1mentioning

confidence: 99%

Ca2+-dependent Interface Formation in Fibrillin-1

Jensen

Corbett

Knott

et al. 2005

Journal of Biological Chemistry

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The calcium-binding epidermal growth factor-like (cbEGF) domain is a common structural motif in extracellular and transmembrane proteins. K d values for Ca 2؉ vary from the millimolar to nanomolar range; however the molecular basis for this variation is poorly understood. We have measured K d values for six fibrillin-1 cbEGF domains, each preceded by a transforming growth factor ␤-binding protein-like (TB) domain. Using NMR and titration with chromophoric chelators, we found that K d values varied by five orders of magnitude. Interdomain hydrophobic contacts between TB-cbEGF domains were studied by site-directed mutagenesis and could be correlated directly with Ca 2؉ affinity. Furthermore, in TB-cbEGF pairs that displayed high-affinity binding, NMR studies showed that TB-cbEGF interface formation was strongly Ca 2؉ -dependent. We suggest that Ca 2؉ affinity is a measure of interface formation in both homologous and heterologous cbEGF domain pairs, thus providing a measure of flexibility in proteins with multiple cbEGF domains. These data highlight the versatile role of the cbEGF domain in fine tuning the regional flexibility of proteins and provide new constraints for the organization of fibrillin-1 within 10؊12-nm microfibrils of the extracellular matrix.The Ca 2ϩ -binding epidermal growth factor-like (cbEGF) 1 domain (see Fig. 1a) is an abundant structural motif found in many extracellular and transmembrane proteins. Many of these proteins, and particularly those found in the extracellular matrix, are required to withstand biomechanical forces and are involved in extensive protein-protein interactions. One of these proteins, fibrillin-1, is a 350-kDa Ca 2ϩ -binding glycoprotein that constitutes the major structural component of the 10 -12-nm microfibrils of the extracellular matrix (1). It has a highly modular domain organization dominated by 43 cbEGF domains and seven transforming growth factor ␤-binding protein-like (TB) domains (see Fig. 1b). Other domains include four non-Ca 2ϩ -binding epidermal growth factor domains, two hybrid domains, unique N and C termini, and a proline-rich sequence (2). Mutations in the fibrillin-1 gene result in Marfan syndrome and related disorders (3, 4). Ultrastructurally, when viewed by rotary shadowing, microfibrils appear as beaded filaments with an interbead distance of 56 nm (5). Although the exact arrangement of fibrillin molecules in the microfibrils is unknown, current models based on structural and antibody localization data suggest that fibrillin forms either staggered parallel arrays of extended molecules (6) or that fibrillin monomers are folded so that each monomer spans one interbead distance (7). Fibrillin-1 cbEGF domains occur in multiple tandem repeats, usually separated by a TB domain. The solution structures of cbEGF domain pairs (8, 9) and hydrodynamic studies of fulllength and recombinant fibrillin-1 fragments (10) have shown that the binding of Ca 2ϩ to these regions stabilizes the rod-like arrangement of these fragments.15 N backbone relaxation data for ...

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Section: Ca 2ϩ -Dependent Interface Formation In Fibrillin-1mentioning

confidence: 99%

Ca2+-dependent Interface Formation in Fibrillin-1

Jensen

Corbett

Knott

et al. 2005

Journal of Biological Chemistry

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“…3 nMFS is usually caused by de novo mutations in a region of the FBN1 gene on chromosome 15q21.1 between exons 24 and 32. [4][5][6] FBN1 consists of 65 exons encoding a 2871 amino-acid protein that contains 47 epidermal growth factor (EGF)-like repeats. Forty-three of these EGF modules satisfy the consensus sequence for calcium binding (cb-EGF) that mediates protein-protein interactions.…”

Section: Discussionmentioning

confidence: 99%

A novel mutation of the fibrillin-1 gene in a newborn with severe Marfan syndrome

et al. 2008

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“…It is determined by heterozygous mutations in the FBN1 gene (15q21.1) encoding for fibrillin 1 protein, which is a component of collagen [9]. It is inherited as an autosomal dominant with variable clinical expression; about 25% of cases are sporadic, due to de novo mutations correlated with advanced paternal age.…”

Section: Marfan Syndromementioning

confidence: 99%