Severe aortopathy due to fibulin-4 deficiency: molecular insights, surgical strategy, and a review of the literature

Hebson, Camden; Coleman, Karlene; Clabby, Martha L.; Sallee, Denver; Shankar, Suma P.; Loeys, Bart; Laer, Lut Van; Kogon, Brian

doi:10.1007/s00431-013-2217-y

Cited by 12 publications

(28 citation statements)

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“…Like the phenotypes of the knockout mice, there are notable differences in the clinical manifestations of ARCL 1A and ARCL 1B patients. A significant proportion of the patients with fibulin-4 mutations die shortly after birth or in early childhood owing to cardiopulmonary failure (Al-Hassnan et al 2012; Dasouki et al 2007; Erickson et al 2012; Hebson et al 2014; Hoyer et al 2009; Hucthagowder et al 2006; Iascone et al 2012; Kappanayil et al 2012; Renard et al 2010; Sawyer et al 2013). The common pathological findings are pulmonary emphysema, arterial tortuosity and aortic aneurysm.…”

Section: Introductionmentioning

confidence: 99%

Forelimb contractures and abnormal tendon collagen fibrillogenesis in fibulin-4 null mice

et al. 2015

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Fibulin-4 is an extracellular matrix glycoprotein essential for elastic fiber formation. Mice deficient in fibulin-4 die perinatally due to severe pulmonary and vascular defects associated with lacking intact elastic fibers. Patients with fibulin-4 mutations demonstrate similar defects and a significant number die shortly after birth or in early childhood owing to cardiopulmonary failure. The patients also demonstrated skeletal and other systemic connective tissue abnormalities, including joint laxity, and flexion contractures of the wrist. A fibulin-4 null mouse strain was generated and used to analyze the roles of fibulin-4 in tendon fibrillogenesis. This mouse model displayed bilateral forelimb contractures, in addition to pulmonary and cardiovascular defects. The forelimb and hindlimb tendons demonstrated a disruption in collagen fibrillogenesis in the absence of fibulin-4 analyzed using transmission electron microscopy. Fewer fibrils were assembled and fibrils were disorganized compared to wild type controls. The organization of developing tenocytes and compartmentalization of the extracellular space also was disrupted. Fibulin-4 was co-localized with fibrillin-1 and fibrillin-2 in limb tendons using immunofluorescence microscopy. Our studies demonstrate that fibulin-4 plays a role in regulating tendon collagen fibrillogenesis, in addition to its essential function in elastogenesis.

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Section: Introductionmentioning

confidence: 99%

Forelimb contractures and abnormal tendon collagen fibrillogenesis in fibulin-4 null mice

et al. 2015

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“…A total of 12 distinct FBLN4 pathogenic mutations have been reported thus far (3,4,(15)(16)(17)(18)(19)(20)(21)(22). The mutations fall into two groups: nine missense and three frameshift mutations.…”

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confidence: 99%

Fibulin-4 E57K Knock-in Mice Recapitulate Cutaneous, Vascular and Skeletal Defects of Recessive Cutis Laxa 1B with both Elastic Fiber and Collagen Fibril Abnormalities

Igoucheva

Alexeev

Halabi

et al. 2015

Journal of Biological Chemistry

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Background: Mutations in fibulin-4 cause autosomal recessive cutis laxa 1B, characterized by loose skin with vascular, lung, and skeletal abnormalities. Results: A mouse strain carrying a recurrent fibulin-4 missense mutation was generated and characterized. Conclusion: Mutant mice recapitulate the complete clinical features of the disease. Significance: The study provides the first evidence that fibulin-4 regulates collagen fibrillogenesis.

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“…In humans or mouse models with arterial tortuosity syndrome (Cheng et al, 2009; Coucke et al, 2006), Loeys-Dietz syndrome (Gallo et al, 2014; Loeys et al, 2006), Marfan syndrome (Morris et al, 2011), with mutations in genes of the TGFβ signaling pathway [ SMAD3 (van de Laar et al, 2011, 2012), TGFB2 (Lindsay et al, 2012), PRKG1 (Guo et al, 2013)] or with mutations in genes directly involved in elastogenesis [ EFEMP2 (Hebson et al, 2014), Fbln5 (Nakamura et al, 2002; Yanagisawa et al, 2002), Ltbp4 (Bultmann-Mellin et al, 2015), Eln (Wagenseil et al, 2009)], aortic or arterial tortuosity is a commonly described feature. Increased aortic tortuosity is associated with a poorer prognosis in aortic diseases (Franken et al, 2015; Hatakeyama et al, 2001; Morris et al, 2011; Shirali et al, 2013), but the detailed mechanisms leading to tortuosity are still unknown (Morris, 2015).…”

Section: Discussionmentioning

confidence: 99%

Function of Ltbp-4L and fibulin-4 in survival and elastogenesis in mice

Bultmann-Mellin

Essers

Heijingen

et al. 2016

Disease Models &Amp; Mechanisms

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LTBP-4L and LTBP-4S are two isoforms of the extracellular matrix protein latent-transforming growth factor beta-binding protein 4 (LTBP-4). The mutational inactivation of both isoforms causes autosomal recessive cutis laxa type 1C (ARCL1C) in humans and an ARCL1C-like phenotype in Ltbp4−/− mice, both characterized by high postnatal mortality and severely affected elastogenesis. However, genetic data in mice suggest isoform-specific functions for Ltbp-4 because Ltbp4S−/− mice, solely expressing Ltbp-4L, survive to adulthood. This clearly suggests a requirement of Ltbp-4L for postnatal survival. A major difference between Ltbp4S−/− and Ltbp4−/− mice is the matrix incorporation of fibulin-4 (a key factor for elastogenesis; encoded by the Efemp2 gene), which is normal in Ltbp4S−/− mice, whereas it is defective in Ltbp4−/− mice, suggesting that the presence of Ltbp-4L might be required for this process. To investigate the existence of a functional interaction between Ltbp-4L and fibulin-4, we studied the consequences of fibulin-4 deficiency in mice only expressing Ltbp-4L. Resulting Ltbp4S−/−;Fibulin-4R/R mice showed a dramatically reduced lifespan compared to Ltbp4S−/− or Fibulin-4R/R mice, which survive to adulthood. This dramatic reduction in survival of Ltbp4S−/−;Fibulin-4R/R mice correlates with severely impaired elastogenesis resulting in defective alveolar septation and distal airspace enlargement in lung, and increased aortic wall thickness with severely fragmented elastic lamellae. Additionally, Ltbp4S−/−;Fibulin-4R/R mice suffer from aortic aneurysm formation combined with aortic tortuosity, in contrast to Ltbp4S−/− or Fibulin-4R/R mice. Together, in accordance with our previous biochemical findings of a physical interaction between Ltbp-4L and fibulin-4, these novel in vivo data clearly establish a functional link between Ltbp-4L and fibulin-4 as a crucial molecular requirement for survival and elastogenesis in mice.

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Severe aortopathy due to fibulin-4 deficiency: molecular insights, surgical strategy, and a review of the literature

Abstract: Better understanding of the importance of transforming growth factor beta signaling in the pathophysiology of aortopathies such as ARCL 1B has led to targeted medical therapies. Specific surgical techniques can lead to optimal outcomes in these patients.

Cited by 12 publications

References 10 publications

Forelimb contractures and abnormal tendon collagen fibrillogenesis in fibulin-4 null mice

Forelimb contractures and abnormal tendon collagen fibrillogenesis in fibulin-4 null mice

Fibulin-4 E57K Knock-in Mice Recapitulate Cutaneous, Vascular and Skeletal Defects of Recessive Cutis Laxa 1B with both Elastic Fiber and Collagen Fibril Abnormalities

Function of Ltbp-4L and fibulin-4 in survival and elastogenesis in mice

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