A Novel Splice Variant in the N-propeptide of COL5A1 Causes an EDS Phenotype with Severe Kyphoscoliosis and Eye Involvement

Background: The Ehlers-Danlos Syndrome (EDS) is a heritable connective tissue disorder characterized by hyperextensible skin, joint hypermobility and soft tissue fragility. The classic subtype of EDS is caused by mutations in one of the type V collagen genes (COL5A1 and COL5A2). Most mutations affect the type V collagen helical domain and lead to a diminished or structurally abnormal type V collagen protein. Remarkably, only two mutations were reported to affect the extended, highly conserved N-propeptide domain, which plays an important role in the regulation of the heterotypic collagen fibril diameter. We identified a novel COL5A1 N-propeptide mutation, resulting in an unusual but severe classic EDS phenotype and a remarkable splicing outcome. Methodology/Principal Findings: We identified a novel COL5A1 N-propeptide acceptor-splice site mutation (IVS6-2A>G, NM_000093.3_c.925-2A>G) in a patient with cutaneous features of EDS, severe progressive scoliosis and eye involvement. Two mutant transcripts were identified, one with an exon 7 skip and one in which exon 7 and the upstream exon 6 are deleted. Both transcripts are expressed and secreted into the extracellular matrix, where they can participate in and perturb collagen fibrillogenesis, as illustrated by the presence of dermal collagen cauliflowers. Determination of the order of intron removal and computational analysis showed that simultaneous skipping of exons 6 and 7 is due to the combined effect of delayed splicing of intron 7, altered pre-mRNA secondary structure, low splice site strength and possibly disturbed binding of splicing factors. Conclusions/Significance: We report a novel COL5A1 N-propeptide acceptor-splice site mutation in intron 6, which not only affects splicing of the adjacent exon 7, but also causes a splicing error of the upstream exon 6. Our findings add further insights into the COL5A1 splicing order and show for the first time that a single COL5A1 acceptor-splice site mutation can perturb splicing of the upstream exon

Ustekinumab in Psoriasis Immunopathology with Emphasis on the Th17-IL23 Axis: A Primer

Psoriasis is a chronic relapsing immunoinflammatory dermatosis that is commonly associated with systemic comorbidities. The pathogenic importance of interleukin (IL)-12 and IL-23 is beyond doubt, as well as the involvement of T helper cells (Th)1 and Th17 cells. There is upregulation of the p40 subunit shared by IL-12 and IL-23 and of the IL-23 p19 subunit, but not an increased expression of the IL-12 p35 subunit. This indicates that IL-23 appears more involved than IL-12 in the pathogenesis of psoriatic plaques. Ustekinumab is a fully human monoclonal antibody of the immunoglobulin (Ig) G1 class targeting the p40 subunit common to both IL-12 and IL-23, thus inhibiting both IL-12 and IL-23 receptor-mediated signalling. Ustekinumab is part of the recent biologic therapies active in psoriasis, autoimmune arthritides, and inflammatory bowel diseases

Cervical artery dissection: An atypical presentation with Ehlers-Danlos-like collagen pathology?

The authors took skin biopsies of the macroscopically normal skin of seven consecutive patients with spontaneous cervical artery dissection (SCAD). Histologically, alterations of the collagen and elastic fiber networks were found in six patients. In five, the histologic, immunohistochemical, and ultrastructural changes were similar to those usually found in Ehlers-Danlos syndrome (EDS). This suggests that SCAD is frequently associated with the dermal alterations seen in EDS

How I explore ... the skin functional involvement in scleroderma

peer reviewedScleroderma refers to distinct clinical presentations sharing in common a sclerotic process most often clinically obvious on the skin. The involvement possibly affects the skin alone in morphea or in combination with internal lesions in systemic sclerosis. Some objective and non-invasive functional assessments are useful for better appreciating the severity and evolution of the disease, as well as to monitor the therapeutic efficacy. In this endeavour, in vivo measurements of the skin mechanical properties are unsurprisingly informative

Cyanoacrylate Skin Surface Stripping and the 3S-Biokit Advent in Tropical Dermatology: A Look from Liège

In the dermatopathology field, some simple available laboratory tests require minimum equipment for establishing a diagnosis. Among them, the cyanoacrylate skin surface stripping (CSSS), formerly named skin surface biopsy or follicular biopsy, represents a convenient low cost procedure. It is a minimally invasive method collecting a continuous sheet of stratum corneum and horny follicular casts. In the vast majority of cases, it is painless and is unassociated with adverse events. CSSS can be performed in subjects of any age. The method has a number of applications in diagnostic dermatopathology and cosmetology, as well as in experimental dermatology settings. A series of derived analytic procedures include xerosis grading, comedometry, corneofungimetry, corneodynamics of stratum corneum renewal, corneomelametry, corneosurfametry, and corneoxenometry

How I explore... the preterm premature rupture of fetal membranes by the ultrastructural examination of the skin

peer reviewedThe etiology of recurrent preterm premature rupture of fetal membranes (PPROM) is varied. Skin biopsies were performed in women who presented recurrent PPROM of unknown origin, searching for a possible general expression of a connective tissue disorder. In the majority of cases, ultrastructural abnormalities were found in collagen bundles and fibrils, as well as in elastic fibres. In conclusion, some types of recurrent PPROM are probably the expression of a generalized connective tissue disorder. The genetic alteration remains to be explored

How I treat....corns and callosities.

peer reviewedCorns and callosities are the expression of a peculiar aspect of mecanobiology of the foot. They are more frequent with ageing, particularly in women. These lesions represent a risk factor for the diabetic foot. Prevention measures are important to follow in predisposed individuals. Several medicinal and non medicinal treatments have proven their efficacy

Skin ultrastructural similarities between fibromyalgia and Ehlers-Danlos syndrome hypermobility type

peer reviewedFibromyalgia (FM) and hypermobility type Ehlers-Danlos syndrome (EDSH) share a series of common clinical signs. A clinical distinction between both diseases is occasionally difficult to be established. The physical changes observed in the mechanical properties of skin and joints do not distinctly distinguish these disorders. In addition, similar ultrastructural dermal changes are observed in both EDSH and some FM cases. The molecular alterations remain largely undisclosed in both diseases. As a result, EDSH remains undiagnosed in some FM patients. This condition deteriorates quality of life and possibly leads to prominent health problems

Gaia, light and the biosphere.

peer reviewedSome aspects of life are tightly bound to light exposure. Photosynthesis, chronobiology and various manifestations of the socio-cultural behaviour are typical examples

Cutaneous photobiology.

peer reviewedThe integration of the various cell reactions with ultraviolet light is modulated by the phototypes. It is responsible for photo-immunological processes and for photocancerogenesis