Genetic Heterogeneity of Cutis Laxa: A Heterozygous Tandem Duplication within the Fibulin-5 (FBLN5) Gene

Markova, Dessislava; Zou, Yaqun; Ringpfeil, Franziska; Sasaki, Takako; Kostka, Günter; Timpl, Rupert; Uitto, Jouni; Chu, Mon‐Li

doi:10.1086/373940

Cited by 147 publications

(100 citation statements)

References 22 publications

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“…The similar appearance of fbn42/2 mouse lamellae and poorly crosslinked chick lamellae suggests that fibulin-4 facilitates cross-linking of elastin at some stage in the assembly process. Like fibulin-4, mutations in the fibulin-5 gene have also been linked to cutis laxa (Loeys et al, 2002;Markova et al, 2003;Hu et al, 2006). Fibulin-5 knockout (fbln52/2) mice show similar phenotypes to the fibulin-42/2 mice, but with less severity as they live a normal lifespan.…”

Section: Fibulinsmentioning

confidence: 99%

New insights into elastic fiber assembly

Wagenseil

Mecham

2007

Birth Defects Research Pt C

357

354

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Elastic fibers provide recoil to tissues that undergo repeated stretch, such as the large arteries and lung. These large extracellular matrix (ECM) structures contain numerous components, and our understanding of elastic fiber assembly is changing as we learn more about the various molecules associated with the assembly process. The main components of elastic fibers are elastin and microfibrils. Elastin makes up the bulk of the mature fiber and is encoded by a single gene. Microfibrils consist mainly of fibrillin, but also contain or associate with proteins such as microfibril associated glycoproteins (MAGPs), fibulins, and EMILIN-1. Microfibrils were thought to facilitate alignment of elastin monomers prior to cross-linking by lysyl oxidase (LOX). We now know that their role, as well as the overall assembly process, is more complex. Elastic fiber formation involves elaborate spatial and temporal regulation of all of the involved proteins and is difficult to recapitulate in adult tissues. This report summarizes the known interactions between elastin and the microfibrillar proteins and their role in elastic fiber assembly based on in vitro studies and evidence from knockout mice. We also propose a model of elastic fiber assembly based on the current data that incorporates interactions between elastin, LOXs, fibulins and the microfibril, as well as the pivotal role played by cells in structuring the final functional fiber. Birth Defects Research (Part C) 81:229-240,

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Section: Fibulinsmentioning

confidence: 99%

New insights into elastic fiber assembly

Wagenseil

Mecham

2007

Birth Defects Research Pt C

357

354

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“…Some patients carry mutations in the elastin (ELN) or fibulin 5 (FBLN5) gene. 5,6 Autosomal recessive CL (ARCL) is the most prevalent and variable form of inherited neonatal CL. ARCL is divided in three major groups: type 1, 2 and 3 (ARCL1, MIM 219100; ARCL2A, MIM 219200; ARCL2B, MIM 612940; WSS, MIM 278250; ARCL3A, MIM 219150; ARCL 3B, MIM 614438; geroderma osteodysplasticum (GO), MIM 231070; De Barsy Syndrome (DBS), MIM 219150; macrocephaly, alopecia, CL, scoliosis syndrome (MACS), MIM 613075).…”

Section: Introductionmentioning

confidence: 99%

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

et al. 2013

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Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL. From a cohort of 26 children, we confirmed mutations in genes associated with ARCL in 16 children (14 probands), including 12 novel mutations. Abnormal glycosylation and gyration abnormalities were mostly, but not always associated with ATP6V0A2 mutations. Epilepsy was most common in ATP6V0A2 defects. Corpus callosum dysgenesis was associated with PYCR1 and ALDH18A1 mutations. Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects. Metabolic markers of mitochondrial dysfunction were found in one patient with PYCR1 mutations. So far unreported white matter abnormalities were found associated with GORAB and RIN2 mutations. We describe a large cohort of CL patients with neurologic involvement. Migration defects and corpus callosum hypoplasia were not always diagnostic for a specific genetic defect in CL. All patients with ATP6V0A2 defects had abnormal glycosylation. To conclude, central nervous system and metabolic abnormalities were discriminatory in this genetically heterogeneous group, although not always diagnostic for a certain genetic defect in CL.

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“…Fibulins are widespread components of ECM and participate in diverse supramolecular structures with binding sites for several proteins including tropoelastin, fibrillin and proteoglycans. Phenotypes previously associated with mutations in fibulin genes include Malattia Leventinese and Doyne honeycomb retinal dystrophy (fibulin 3) [Stone et al, 1999], cutis laxa (fibulin 5) [Loeys et al, 2002;Markova et al, 2003], and ARMD in a single family (fibulin 6) [Schultz et al, 2003]. …”

Section: Introductionmentioning

confidence: 99%

Reduced secretion of fibulin 5 in age-related macular degeneration and cutis laxa

et al. 2006

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Age-related macular degeneration (ARMD) is the leading cause of irreversible visual loss in the Western world, affecting approximately 25 million people worldwide. The pathogenesis is complex and missense mutations in FBLN5 have been reported in association with ARMD. We have investigated the role of fibulin 5 in ARMD by completing the first European study of the gene FBLN5 in ARMD (using 2 European cohorts of 805 ARMD patients and 279 controls) and by determining the functional effects of the missense mutations on fibulin 5 expression. We also correlated the FBLN5 genotype with the ARMD phenotype. We found two novel sequence changes in ARMD patients that were absent in controls and expressed these and the other nine reported FBLN5 mutations associated with ARMD and two associated with the autosomal recessive disease cutis laxa. Fibulin 5 secretion was significantly reduced (P<0.001) for four ARMD (p.G412E, p.G267S, p.I169 T, and p.Q124P) and two cutis laxa (p.S227P, p.C217R) mutations. These results suggest that some missense mutations associated with ARMD lead to decreased fibulin 5 secretion with a possible corresponding reduction in elastinogenesis. This study confirms the previous work identifying an association between FBLN5 mutations and ARMD and for the first time suggests a functional mechanism by which these mutations can lead to ARMD. It further demonstrates that FBLN5 mutations can be associated with different phenotypes of ARMD (not limited to the previously described cuticular drusen type). Such knowledge may ultimately lead to the development of novel therapies for this common disease.

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Genetic Heterogeneity of Cutis Laxa: A Heterozygous Tandem Duplication within the Fibulin-5 (FBLN5) Gene

Cited by 147 publications

References 22 publications

New insights into elastic fiber assembly

New insights into elastic fiber assembly

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

Reduced secretion of fibulin 5 in age-related macular degeneration and cutis laxa

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