Novel de novo nonsense mutation of FBN1 gene in a patient with Marfan syndrome

Song, Young Ho; Kim, Gu-Hwan; Yoo, Han‐Wook; Kim, June-Bum

doi:10.1007/s12041-012-0165-3

Cited by 9 publications

(6 citation statements)

References 4 publications

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“…Dilatation and dissection of the aorta is a manifestation. A novel de novo nonsense mutation in fibrillin-1 is seen in a Marfan disease carrier, viz:p. Gln2553X, presenting with cardinal disease features [55].…”

Section: Vascular and Heart Diseases -Aneurysmmentioning

confidence: 99%

Repurposing Amlexanox as a Run the Red Light Cure-All with Readthrough a No-Nonsense Approach to Personalised Medicine

Loudon¹

2013

J Bioanal Biomed

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Catalogue of somatic mutations in cancerContinuing with the cancer theme, even a brief examination of COSMIC -Catalogue of somatic mutations in cancer [1] shows the weight PTC mutations carry in the causation of a whole range of cancers through TS inactivation. As such, COSMIC provides for an excellent AbstractThe burden of inherited diseases in terms of congenital defects and cancer predisposition in addition to a multitude of neurological, cardiovascular and other organ diseases arising sporadically during life is enormous on the individual, immediate family and society globally. I approach this major burden to human society by invoking the powerful technology behind read-through, whereby disease-causing substitution nonsense mutations, oftentimes at the root of human diseases, are rescued. Further, the importance of nonsense mutations in the realm of developmental factors linked to cancer stem cell maintenance is presented. The methodology behind the technique is given and proof of concept behind its use ex vivo and in clinical trials. The discovery of a novel read-through drug, Amlexanox, which has been in use for over twenty years in dentistry for oral ulcerations, represents a next generation read-through agent. This agent has been demonstrated in cell lines to correct functional loss in cystic fibrosis CFTR, dystrophin and the tumour suppressor, p53. Its novel ability to inhibit nonsense mediated decay is discussed. Amlexanox is therefore presently ready for testing in a wide variety of in vivo models of human diseases and also in clinical trials. Given the safety profile of Amlexanox and ex vivo efficacy in studies thus far it is envisaged that this accepted medication shall successfully debut as an all-purpose agent for the prevention and management of human diseases.

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Section: Vascular and Heart Diseases -Aneurysmmentioning

confidence: 99%

Repurposing Amlexanox as a Run the Red Light Cure-All with Readthrough a No-Nonsense Approach to Personalised Medicine

Loudon¹

2013

J Bioanal Biomed

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“…Recent studies have implicated a potential hormone, named asprosin, encoded by the FBN1 locus as a mediator of the lipodystrophy phenotype (Duerrschmid et al, 2017;Romere et al, 2016). All previously reported MPLS individuals consistently harbor heterozygous truncating mutations in exon 64, which leads to the formation of premature stop codons in the C-terminal domain of FBN1 (Garg & Xing, 2014;Goldblatt et al, 2011;Jacquinet et al, 2014;Passarge et al, 2016;Romere et al, 2016;Song, Kim, Yoo, & Kim, 2012).…”

Section: Introductionmentioning

confidence: 99%

Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1

Lin

Liu

et al. 2019

Molec Gen & Gen Med

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Background The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid–progeroid–lipodystrophy syndrome (MPLS). Methods We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. Results We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense‐mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro. Conclusion We provide direct evidence that a dominant‐negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

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“…MPL syndrome is a novel fibrillinopathy and a disease that has very rarely been reported in the clinic. All MPL patients carry mutations in exon 64, which leads to a premature stop codon in the C-terminus of FBN1 ( Garg and Xing, 2014 ; Goldblatt et al, 2011 ; Graul-Neumann et al, 2010 ; Jacquinet et al, 2014 ; Romere et al, 2016 ; Song et al, 2012 ). Thoracic aortic aneurysm/dissection (TAAD), ectopia lentis, and systemic features with score ≥7 are the main clinical criteria of classical MFS, while the most apparent features of MPL syndrome are a progeroid appearance and lipodystrophy ( Chandra et al, 2015 ; Jacquinet et al, 2014 ; Passarge et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit

Chen

Yao

Yang

et al. 2018

Disease Models &Amp; Mechanisms

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Various clinical differences have been observed between patients with the FBN1 gene mutation and those with the classical Marfan phenotype. Although FBN1 knockout (KO) or dominant-negative mutant mice are widely used as an animal model for Marfan syndrome (MFS), these mice cannot recapitulate the genotype/phenotype relationship of Marfanoid-progeroid-lipodystrophy (MPL) syndrome, which is caused by a mutation in the C-terminus of fibrillin-1, the penultimate exon of the FBN1 gene. Here, we describe the generation of a rabbit MPL model with C-terminal truncation of fibrillin-1 using a CRISPR/Cas9 system. FBN1 heterozygous (FBN1 Het) rabbits faithfully recapitulated the phenotypes of MFS, including muscle wasting and impaired connective tissue, ocular syndrome and aortic dilation. Moreover, skin symptoms, lipodystrophy, growth retardation and dysglycemia were also seen in these FBN1 Het rabbits, and have not been reported in other animal models. In conclusion, this novel rabbit model mimics the histopathological changes and functional defects of MPL syndrome, and could become a valuable model for studies of pathogenesis and drug screening for MPL syndrome.

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Novel de novo nonsense mutation of FBN1 gene in a patient with Marfan syndrome

Cited by 9 publications

References 4 publications

Repurposing Amlexanox as a Run the Red Light Cure-All with Readthrough a No-Nonsense Approach to Personalised Medicine

Repurposing Amlexanox as a Run the Red Light Cure-All with Readthrough a No-Nonsense Approach to Personalised Medicine

Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1

Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit

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