A Point Mutation Creating an ExtraN-Glycosylation Site in Fibrillin-1 Results in Neonatal Marfan Syndrome

Lönnqvist, Lasse; Karttunen, Leena; Rantamäki, Terhi; Kielty, Cay M.; Raghunath, Michael; Peltonen, Leena

doi:10.1006/geno.1996.0492

Cited by 50 publications

(37 citation statements)

References 5 publications

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“…This was first reported in an individual with neonatal Marfan syndrome due to a missense mutation in exon 25 (I1048T), and experimental evidence was given that the novel N-glycosylation site was actually utilized [Lönnqvist et al, 1996]. Four other mutations potentially creating a novel N-glycosylation site have been published (I1048T, I1909T (2x), I2585T); references provided in Robinson et al [2002] and an analogous mutation of the fibrillin-2 gene was identified in a patient with congenital contractural arachnodactyly [Park et al, 1998].…”

Section: Discussionmentioning

confidence: 95%

TGGE screening of the entireFBN1coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies

et al. 2002

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Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome (MFS), an autosomal dominant heritable disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. FBN1 mutations have also been identified in a series of related disorders of connective tissue collectively termed type-1 fibrillinopathies. We have developed temperature-gradient gel electrophoresis (TGGE) assays for all 65 FBN1 exons, screened 126 individuals with MFS, other type-1 fibrillinopathies, and other potentially related disorders of connective tissue for FBN1 mutations, and identified a total of 53 mutations, of which 33 are described here for the first time. Several mutations were identified in individuals with fibrillinopathies other than classic Marfan syndrome, including aneurysm of the ascending aorta with only minor skeletal anomalies, and several individuals with only skeletal and ocular involvement. The mutation detection rate in this study was 42% overall, but was only 12% in individuals not fulfilling the diagnostic criteria for MFS, suggesting that clinical overdiagnosis is one reason for the low detection rate observed for FBN1 mutation analysis.

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Section: Discussionmentioning

confidence: 95%

TGGE screening of the entireFBN1coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies

et al. 2002

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“…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. 1) of cbEGF11.…”

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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“…Of note, disorders involving mutations in residues that permit differential Nlinked glycosylation are rare, however, Marfan syndrome can result from an additional N-linked glycosylation site in Fibrillin-1 (FBN1) [Lonnqvist et al, 1996], and a mutation that removes an N-linked glycosylation site in the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTAG) gene causes mucolipidosis type III [Tiede et al, 2004].…”

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confidence: 99%