Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3′ end of FBN1 gene

Jacquinet, Adeline; Verloès, Alain; Callewaert, Bert; Coremans, Christine; Coucke, Paul; Paepe, Anne De; Kornak, Uwe; Lebrun, Frédéric; Lombet, Jacques; Pierard, Gérald; Robinson, Peter N.; Symoens, Sofie; Maldergem, Lionel Van; Debray, François-Guillaume

doi:10.1016/j.ejmg.2014.02.012

Cited by 41 publications

(49 citation statements)

References 21 publications

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“…In addition, the intracellular retention caused by the single amino acid L2780P substitution (20), which affects a highly conserved leucine, suggests that the function of the propeptide is dependent on its native structure and/or interactions. Recently a correlation has been established between a subset of mutations affecting the fibrillin-1 C terminus and a neonatal, progeroid form of MFS (30)(31)(32)(33)(34). All of these mutations result in a frameshift with the introduction of a stop codon before the sequence encoding the C-terminal furin cleavage site (33).…”

Section: Discussionmentioning

confidence: 99%

“…Recently a correlation has been established between a subset of mutations affecting the fibrillin-1 C terminus and a neonatal, progeroid form of MFS (30)(31)(32)(33)(34). All of these mutations result in a frameshift with the introduction of a stop codon before the sequence encoding the C-terminal furin cleavage site (33). The transcripts in these cases are unlikely to undergo nonsense-mediated decay (24) and the resulting polypeptides would be similar to the N-2Cys and N-cb43 variants described here.…”

Section: Discussionmentioning

confidence: 99%

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C-terminal propeptide is required for fibrillin-1 secretion and blocks premature assembly through linkage to domains cbEGF41-43

Jensen

Aspinall

Handford

2014

Proc. Natl. Acad. Sci. U.S.A.

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Fibrillin microfibrils are 10-12 nm diameter, extracellular matrix assemblies that provide dynamic tissues of metazoan species with many of their biomechanical properties as well as sequestering growth factors and cytokines. Assembly of fibrillin monomers into microfibrils is thought to occur at the cell surface, with initial steps including proprotein processing, multimerization driven by the C terminus, and the head-to-tail alignment of adjacent molecules. At present the mechanisms that regulate microfibril assembly are still to be elucidated. We have used structure-informed protein engineering to create a recombinant, GFP-tagged version of fibrillin-1 (GFP-Fbn) to study this process. Using HEK293T cells transiently transfected with GFP-Fbn constructs, we show that (i) the C-terminal propeptide is an essential requirement for the secretion of fulllength fibrillin-1 from cells; (ii) failure to cleave off the C-terminal propeptide blocks the assembly of fibrillin-1 into microfibrils produced by dermal fibroblasts; and (iii) the requirement of the propeptide for secretion is linked to the presence of domains cbEGF41-43, because either deletion or exchange of domains in this region leads to cellular retention. Collectively, these data suggest a mechanism in which the propeptide blocks a key site at the C terminus to prevent premature microfibril assembly.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

C-terminal propeptide is required for fibrillin-1 secretion and blocks premature assembly through linkage to domains cbEGF41-43

Jensen

Aspinall

Handford

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…6,7 Six recent reports describe seven patients with a newly recognized syndrome, the clinical features of which overlap with those of congenital MFS, progeroid syndromes, and lipodystrophy. [8][9][10][11][12][13] All seven individuals harbor a disease-causing mutation in exon 64, the penultimate exon of the FBN1 gene (Table 1).…”

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confidence: 99%

“…[9][10][11][12][13] In all seven patients, the mutation is located in exon 64 of the FBN1 gene, as summarized in Table 1. All were de novo; two patients carried the same splice site mutation.…”

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confidence: 99%

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Marfanoid–progeroid–lipodystrophy syndrome: a newly recognized fibrillinopathy

2016

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We review six previous reports between 2000 and 2014 of seven unrelated patients with mutations in the FBN1 gene affecting function. All mutations occurred in exon 64 of the FBN1 gene. A distinctive phenotype consisting of partial manifestations of Marfan syndrome, a progeroid facial appearance, and clinical features of lipodystrophy was present in all individuals. We suggest that this previously unknown genotype/phenotype relationship constitutes a new fibrillinopathy for which the name marfanoid-progeroid-lipodystrophy syndrome would be appropriate.

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