A Recurring FBN1 Gene Mutation in Neonatal Marfan Syndrome

Jacobs, A.; Toudjarska, Iva; Racine, Andrew D.; Tsipouras, Petros; Kilpatrick, Michael W.; Shanske, Alan

doi:10.1001/archpedi.156.11.1081

Cited by 43 publications

(33 citation statements)

References 17 publications

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“…27 In neonatal Marfan syndrome, a severe form of the disease, emphysema, is common. 21,23 It should be noted that the presence of emphysema in patients with Marfan syndrome may very well be underestimated. Patients are generally not examined for emphysema/COPD.…”

Section: Discussionmentioning

confidence: 99%

“…In man, developmental emphysema has been noticed in patients with Marfan syndrome, an autosomal disorder caused by mutations in the gene encoding fibrillin-1. [19][20][21][22][23][24][25][26][27] In mice, disruption of the fibrillin-1 gene results in developmental emphysema. The tight skin mouse, characterized by tandem duplication of 30-40 kb in the gene encoding fibrillin-1, develops emphysematous lesions that are in many ways similar to those observed in humans.…”

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confidence: 99%

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Aberrant fibrillin-1 expression in early emphysematous human lung: a proposed predisposition for emphysema

et al. 2008

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Parenchymal destruction, airspace enlargement, and loss of elasticity are hallmarks of pulmonary emphysema. Although the basic mechanism is unknown, there is a consensus that malfunctioning of the extracellular matrix is a major contributor to the pathogenesis of emphysema. In this study, we analyzed the expression of the elastic fiber protein fibrillin-1 in a large number (n ¼ 69) of human lung specimens with early-onset emphysema. Specimens were morphologically characterized by the Destructive Index, the Mean Linear Intercept, and the Panel Grading. We observed a strong correlation (Po0.001) of aberrant fibrillin-1 staining with the degree of destruction of lung parenchyma (r ¼ 0.71), airspace enlargement (r ¼ 0.47), and emphysema-related morphological abnormalities (r ¼ 0.69). There were no obvious correlations with age and smoking behavior. Staining for three other extracellular matrix components (type I collagen, type IV collagen, and laminin) was not affected. The aberrant fibrillin-1 staining observed in this study is similar to that observed in Marfan syndrome, a syndrome caused by mutations in the gene encoding fibrillin-1. Strikingly, emphysema is noticed in a number of Marfan patients. This, together with the notion that disruption of the fibrillin-1 gene in mice results in emphysematous lesions, makes fibrillin-1 a strong candidate to be involved in the etiology and pathogenesis of emphysema.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Aberrant fibrillin-1 expression in early emphysematous human lung: a proposed predisposition for emphysema

et al. 2008

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“…Although mutations in exons 24-32 have been reported in patients with neonatal MFS [Kainulainen et al, 1994;Putnam et al, 1996;Booms et al, 1999;Schrijver et al, 1999;Tiecke et al, 2001;Jacobs et al, 2002;Elcioglu et al, 2004;Revencu et al, 2004;ter Heide et al, 2005], mutations in the same region can also cause classical MFS [Schrijver et al, 1999;Tiecke et al, 2001;Loeys et al, 2004]. Missense mutations or small insertion-deletions in exons 24-27 and exon skipping mutations in exons 31 and 32 are especially common in neonatal MFS [Booms et al, 1999;Tiecke et al, 2001].…”

Section: Discussionmentioning

confidence: 99%

“…Described mutations are widespread throughout the gene and largely unique to each family. The most apparent genotype-phenotype correlation is for the neonatal MFS, for which mutations in exons 24-32 have exclusively been reported [Kainulainen et al, 1994;Putnam et al, 1996;Booms et al, 1999;Schrijver et al, 1999;Tiecke et al, 2001;Jacobs et al, 2002;Elçioglu et al, 2004;Revencu et al, 2004;Shinawi et al, 2005;ter Heide et al, 2005]. To our knowledge, all reported patients with neonatal MFS due to heterozygous FBN1 mutations were sporadic.…”

Section: Introductionmentioning

confidence: 86%

Familial neonatal Marfan syndrome due to parental mosaicism of a missense mutation in the FBN1 gene

Tekin

Cengiz

Ayberkin

et al. 2007

American J of Med Genetics Pt A

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We present a family in which three siblings were born with neonatal Marfan syndrome (MFS) to unaffected parents. The clinical findings included joint contractures, large ears, loose skin, ectopia lentis, muscular hypoplasia, aortic root dilatation, mitral and tricuspid valve insufficiency, and pulmonary emphysema. All three siblings died due to cardiorespiratory insufficiency by 2-4 months of age. Screening of the FBN1 gene showed the heterozygous c.3257G > A (p.Cys1086Tyr) mutation in the proband. Mosaicism of the mutation was demonstrated in the somatic cells and in the germ line of the father. Although three examples of parental mosaicism for classical MFS were demonstrated previously, this is the first report of familial occurrence of neonatal MFS due to a heterozygous mutation in FBN1. In conclusion, the p.Cys1086Tyr mutation in FBN1 is consistently associated with neonatal MFS. Parental mosaicism should always be kept in mind when counseling families with MFS.

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“…Histologically, elastic fibres in the emphysematous lung appear fragmented, with a reduced microfibrillar component and evidence of disorganised elastin deposition (Fukuda et al 1989). Evidence for the involvement of fibrillin in the pathogenesis of emphysema comes from the observation of emphysematous lesions in connective tissues disorders such as neonatal (Jacobs et al 2002;Milewicz and Duvic 1994) and adult (Bolande and Tucker 1964;Sayers et al 1975) Marfan syndrome and the tight skin mouse model of hereditary emphysema (Gardi et al 1989). Whilst even in the early stages of human emphysema fragmentation of fibrillin microfibril bundles is evident (Robbesom et al 2008).…”

Section: Pulmonarymentioning

confidence: 99%

Tissue elasticity and the ageing elastic fibre

Sherratt

2009

AGE

269

189

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The ability of elastic tissues to deform under physiological forces and to subsequently release stored energy to drive passive recoil is vital to the function of many dynamic tissues. Within vertebrates, elastic fibres allow arteries and lungs to expand and contract, thus controlling variations in blood pressure and returning the pulmonary system to a resting state. Elastic fibres are composite structures composed of a cross-linked elastin core and an outer layer of fibrillin microfibrils. These two components perform distinct roles; elastin stores energy and drives passive recoil, whilst fibrillin microfibrils direct elastogenesis, mediate cell signalling, maintain tissue homeostasis via TGFβ sequestration and potentially act to reinforce the elastic fibre. In many tissues reduced elasticity, as a result of compromised elastic fibre function, becomes increasingly prevalent with age and contributes significantly to the burden of human morbidity and mortality. This review considers how the unique molecular structure, tissue distribution and longevity of elastic fibres pre-disposes these abundant extracellular matrix structures to the accumulation of damage in ageing dermal, pulmonary and vascular tissues. As compromised elasticity is a common feature of ageing dynamic tissues, the development of strategies to prevent, limit or reverse this loss of function will play a key role in reducing age-related morbidity and mortality.

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A Recurring FBN1 Gene Mutation in Neonatal Marfan Syndrome

Cited by 43 publications

References 17 publications

Aberrant fibrillin-1 expression in early emphysematous human lung: a proposed predisposition for emphysema

Aberrant fibrillin-1 expression in early emphysematous human lung: a proposed predisposition for emphysema

Familial neonatal Marfan syndrome due to parental mosaicism of a missense mutation in the FBN1 gene

Tissue elasticity and the ageing elastic fibre

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