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Molecular-Genetic Basis and Ethiopathogenesic Mechanisms in Cutis Laxa
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Molecular-Genetic Basis and Ethiopathogenesic Mechanisms in Cutis Laxa

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2016) | Viewed by 22863

Special Issue Editors

Prof. Dr. Anne De Paepe

E-Mail Website
Guest Editor
Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, De Pintelaan
Interests: heritable connective tissue disorders; extracellular matrix; connective tissue; cutis laxa; ehlers-danlos syndromes; human genetics
Prof. Dr. Fransiska Malfait

E-Mail Website
Guest Editor
Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
Interests: heritable connective tissue disorders; extracellular matrix; connective tissue; cutis laxa; ehlers-danlos syndromes; human genetics

Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to the cutis laxa (CL) syndromes, a heterogeneous group of rare connective tissue disorders that share the presence of a loose, redundant, and inelastic skin, associated with multisystemic manifestations of variable severity. Both inherited and acquired forms of CL have been described; their common pathogenic basis being the formation of abnormal elastic fibers (EF). The elucidation of the genetic basis of inherited CL forms has shown that the pathogenesis of CL is increasingly complex and that at least three major pathways are involved. These include (1) defects in extracellular matrix (ECM) proteins that are directly involved in EF assembly and that are associated with up-regulation of TGFβ signaling; (2) defects that affect vesicular trafficking and as such perturb modification and secretion of EF components; and (3) defects that affect the metabolic function of the mitochondria. The latter group results in very severe phenotypes with progeroid features, skeletal and ophthalmologic abnormalities, intrauterine growth retardation and intellectual disability. Identification of these genes has not only shed light onto the complex processes underlying EF assembly and ECM functioning, their identification also paves the way towards targeted therapeutic approaches.

For this Special Issue will welcome state-of-the-art articles on the (patho)genetic basis of CL syndromes and high-quality contributions that address research questions that will lead to a deeper understanding of the pathomechanistic pathways involved in perturbed EF assembly. This will provide invaluable information for the development of molecular treatment strategies of these currently intractable diseases.

Prof. Dr. Anne De Paepe
Prof. Dr. Fransiska Malfait
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Autosomal Dominant
  • Autosomal Recessive
  • Cutis laxa
  • Elastic fibers
  • Extracellular matrix
  • Metabolism
  • Mitochondria
  • Protein trafficking
  • TGFβ
  • X-linked inheritance

Published Papers (2 papers)

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Review
Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica
by Ariana Kariminejad, Fariba Afroozan, Bita Bozorgmehr, Alireza Ghanadan, Susan Akbaroghli, Hamid Reza Khorram Khorshid, Faezeh Mojahedi, Aria Setoodeh, Abigail Loh, Yu Xuan Tan, Nathalie Escande-Beillard, Fransiska Malfait, Bruno Reversade, Thatjana Gardeitchik and Eva Morava
Int. J. Mol. Sci. 2017, 18(3), 635; https://doi.org/10.3390/ijms18030635 - 15 Mar 2017
Cited by 20 | Viewed by 14512
Abstract
Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa [...] Read more.
Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa IIA (ARCL2A), cutis laxa IIB (ARCL2B), and geroderma osteodysplastica (GO), have very similar clinical features, complicating accurate diagnosis. Individuals with these conditions often present with cutis laxa, progeroid features, and hyperextensible joints. These conditions also share additional features, such as short stature, hypotonia, and congenital hip dislocation, but the severity and frequency of these findings are variable in each of these cutis laxa syndromes. The characteristic features for ARCL2A are abnormal isoelectric focusing and facial features, including downslanting palpebral fissures and a long philtrum. Rather, the clinical phenotype of ARCL2B includes severe wrinkling of the dorsum of the hands and feet, wormian bones, athetoid movements, lipodystrophy, cataract and corneal clouding, a thin triangular face, and a pinched nose. Normal cognition and osteopenia leading to pathological fractures, maxillary hypoplasia, and oblique furrowing from the outer canthus to the lateral border of the supraorbital ridge are discriminative features for GO. Here we present 10 Iranian patients who were initially diagnosed clinically using the respective features of each cutis laxa syndrome. Each patient’s clinical diagnosis was then confirmed with molecular investigation of the responsible gene. Review of the clinical features from the cases reported from the literature also supports our conclusions. Full article
(This article belongs to the Special Issue Molecular-Genetic Basis and Ethiopathogenesic Mechanisms in Cutis Laxa)
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Review
GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations
by Eva Y. G. De Vilder, Jens Debacker and Olivier M. Vanakker
Int. J. Mol. Sci. 2017, 18(2), 240; https://doi.org/10.3390/ijms18020240 - 25 Jan 2017
Cited by 32 | Viewed by 7107
Abstract
Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding GGCX gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) [...] Read more.
Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding GGCX gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype–phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one GGCX mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations—a frequent problem in orphan diseases—we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype–phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management. Full article
(This article belongs to the Special Issue Molecular-Genetic Basis and Ethiopathogenesic Mechanisms in Cutis Laxa)
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