Clinical and Molecular Delineation of Cutis Laxa Syndromes: Paradigms for Elastic Fiber Homeostasis

Beyens, Aude; Pottie, Lore; Sips, Patrick; Callewaert, Bert

doi:10.1007/978-3-030-80614-9_13

Cited by 5 publications

(4 citation statements)

References 197 publications

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“…13 C- 15 N SEP was dialyzed in H2O after purification and lyophilized. 66 mg of protein were resuspended in 860 µL of PBS buffer and placed in a bath at 40 °C for 15 min for coacervation.…”

Section: Nuclear Magnetic Resonancementioning

confidence: 99%

“…Other arteries are also subject to stenosis in this pathology [17]. In ADCL, patients can suffer from aortic aneurism, pulmonary emphysema, hernia and high skin laxity [15]. Some cases of acquired cutis laxa have also been described, in which the elastic fibers are more susceptible to degradation during inflammatory responses [18].…”

Section: Introductionmentioning

confidence: 99%

“…Elasticity deficiencies can also result from acquired or inherited disorders (reviewed in [13]). Among them, some are directly linked to a defect in the tropoelastin gene, such as Williams Beuren syndrome (WBS) [14] and the autosomal dominant cutis laxa (ADCL) [15]. The most impacted tissues are skin, blood vessels and lungs with a broad range of symptoms.…”

Section: Introductionmentioning

confidence: 99%

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A synthetic elastic protein as molecular prosthetic candidate to strengthen vascular wall elasticity

Hoareau,

Lorion,

Lecoq

et al. 2023

Preprint

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The loss of elasticity is a hallmark of systemic aging or genetic syndromes (e.g. cutis laxa, Williams-Beuren and supravalvular aortic stenosis) with direct consequences on tissue functions, and particularly deleterious when associated to the cardiovascular system. Tissue elasticity is mainly provided by large elastic fibers composed of supramolecular complexes of elastin and microfibrils. In arteries, the mature elastic fibers are located in the media compartment and form concentric elastic lamellar units together with the smooth muscle cells (SMCs). The main function of vascular elastic fibers is to allow extension and recoil of the vessel walls in response to the intraluminal pressure generated by the blood flow following cardiac systole. The synthesis of elastic fibers (elastogenesis) mainly occurs during the last third of fetal life with a peak in the perinatal period and then slowly decreases until the end of growth; as a result, elastic fiber repair is almost non-existent in adults. To date, no treatment exists to restore or repair deficient or degraded elastic fibers. A few pharmacological compounds have been proposed, but their efficacy/side effects balance remains very unfavorable. As an alternative strategy, we developed a synthetic elastic protein (SEP) inspired by the human tropoelastin, the elastin soluble precursor, to provide an elastic molecular prosthesis capable of integrating and reinforcing endogenous elastic fibers.The SEP was easily produced in E. coli and purified by inversed transition cycling method. The resulting 55 kDa protein recapitulates the main physicochemical properties of the tropoelastin as thermal responsiveness, intrinsically disordered structures, and spherical self-assembly. The cross-linked SEP displays linear elastic mechanical properties under uniaxial tension loads. Using a co-culturein vitromodel of the endothelial barrier, our results show that SEP is able to cross the cohesive endothelial monolayer to reach underlying SMCs. Moreover, SEP is processed by SMCs through a lysyl oxidase-dependent mechanism to form fibrillar structures that colocalize with fibrillin-rich microfibrils. The SEP was further characterizedin vivothrough the zebrafish model. The results indicate a global innocuity on zebrafish embryos and an absence of neutrophil recruitment following injection into the yolk sac of zebrafish. Finally, intravenous injection of a fluorescent SEP highlights its deposition in the wall of tortuous vessels which persists for several days after injection of the larvae. Taken together, our results demonstrate for the first time the incorporation of a naked tropoelastin-bioinspired polypeptide in endogenous elastic fibrillar deposits from SMCs, and its recognition by the lysyl- oxidase enzymatic machinery. In absence of toxicity and proinflammatory signal combined to a long-lasting accumulation in vesselsin vivo, the SEP fulfills the first prerequisites for the development of an original biotherapeutic compound addressing the repair of elastic fibers.

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Section: Nuclear Magnetic Resonancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A synthetic elastic protein as molecular prosthetic candidate to strengthen vascular wall elasticity

Hoareau,

Lorion,

Lecoq

et al. 2023

Preprint

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“…Cutis laxa is a group of rare connective tissue disorders characterized by loose and wrinkled skin. It is associated with skeletal and developmental abnormalities and, in some cases, severe systemic impairments (Beyens et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

First report of a short in‐frame biallelic deletion removing part of the EGF‐like domain calcium‐binding motif in LTBP4 and causing autosomal recessive cutis laxa type 1C

Ravel

Comel²,

Wandzel³

et al. 2022

American J of Med Genetics Pt A

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Cutis laxa (CL) is a rare connective tissue disorder characterized by wrinkled, abundant and sagging skin, sometimes associated with systemic impairment. Biallelic alterations in latent transforming growth factor beta-binding protein 4 gene (LTBP4) cause autosomal recessive type 1C cutis laxa (ARCL1C, MIM #613177). The present report describes the case of a 17-months-old girl with cutis laxa together with a literature review of previous ARCL1C cases. Based on proband main clinical signs (cutis laxa and pulmonary emphysema), clinical exome sequencing (CES) was performed and showed a new nine base-pairs homozygous in-frame deletion in LTBP4 gene. RT-PCR and cDNA Sanger sequencing were performed in order to clarify its impact on RNA. This report demonstrates that a genetic alteration in the EGF-like 14 domain calcium-binding motif of LTBP4 gene is likely responsible for cutis laxa in our patient.autosomal recessive cutis laxa type 1C (ARCL1C), calcium-binding epidermal growth factor-like domain, LTBP4, Urban-Rifkin-Davis syndrome (URDS) | INTRODUCTIONCutis laxa is a group of rare connective tissue disorders characterized by loose and wrinkled skin. It is associated with skeletal and developmental abnormalities and, in some cases, severe systemic impairments (Beyens et al., 2021).Connective tissue is a supporting tissue consisting of three components: (1) secretory cells synthetizing ground substance and specific proteins which give connective tissue its characteristics, (2) elastin made elastic fibers, responsible for the skin elastic properties, and collagen made reticular fibers contributing to small blood vessels and soft tissues support, and (3) ground substance.Cutis laxa is the Latin term for sagging or slackened, nonstretchable skin. This wrinkle-like skin can be particularly noticeable on the face, neck, armpits, and limbs. Cutis laxa may be inherited or acquired.Acquired forms most often occur in adulthood, their etiology including infections, drugs, or paraneoplasia (Lewis et al., 2004).Three major groups are individualized based on the inheritance mode: autosomal dominant, autosomal recessive, and X-linked recessive cutis laxa.

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Genetics of Cutis Laxa

Beyens

Callewaert

2023

Encyclopedia of Life Sciences

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Cutis laxa syndromes are a heterogeneous group of multisystem disorders with prominent connective tissue features including loose redundant skin folds, a clinical hallmark shared among all subtypes. The skin laxity results from severe dermal elastic fibre fragmentation. The molecular defects underlying congenital forms of cutis laxa may affect any step in elastic fibre assembly, as illustrated by the identification of pathogenic variants in different extracellular matrix proteins, including elastin, latent transforming growth factor β proteins and fibulins ( ELN , LTBP4 , FBLN4 , FBLN5, LOX, EMILIN1, LTPB1 ), cellular trafficking ( ATP6V0A2, ATP6V1E1, ATP6V1A and ATP7A ) and metabolic processes ( ALDH18A1, PYCR1) . The latter two groups have been referred to as neurometabolic cutis laxa and may present with skeletal and neurological phenotypes in addition to connective tissue manifestations. Key Concepts Elastic fibres (EF) provide resilience and elasticity to the connective tissue and contribute to tissue homeostasis by regulating cytokine signalling and cell–matrix interactions. Elastic fibre synthesis or elastogenesis is a complex spatiotemporally regulated multistep process. Cutis laxa syndromes are a heterogeneous group of multisystem connective tissue disorders that share loose redundant skin folds, that vary significantly in severity and spectrum of the associated clinical manifestations. The molecular defects underlying congenital forms of cutis laxa involve all steps in EF synthesis, affecting different extracellular matrix proteins ( ELN, LTBP4, FBLN4, FBLN5, LOX, EMILIN1, LTBP1 ), cellular trafficking ( ATP6V0A2, ATP6V1E1, ATP6V1A, SCYL1BP1 and ATP7A ) and metabolism ( ALDH18A1, PYCR1 ). Cutis laxa caused by defects in extracellular matrix proteins present with prominent arterial and/or pulmonary abnormalities. Cutis laxa caused by intracellular trafficking disorders and/or metabolic disorders may present with intellectual deficiency, skeletal and/or ocular defects.

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Clinical and Molecular Delineation of Cutis Laxa Syndromes: Paradigms for Elastic Fiber Homeostasis

Cited by 5 publications

References 197 publications

A synthetic elastic protein as molecular prosthetic candidate to strengthen vascular wall elasticity

A synthetic elastic protein as molecular prosthetic candidate to strengthen vascular wall elasticity

First report of a short in‐frame biallelic deletion removing part of the EGF‐like domain calcium‐binding motif in LTBP4 and causing autosomal recessive cutis laxa type 1C

Genetics of Cutis Laxa

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