Cutis laxa: Intersection of elastic fiber biogenesis, TGFβ signaling, the secretory pathway and metabolism

Abstract

Cutis laxa (CL), a disease characterized by redundant and inelastic skin, displays extensive locus heterogeneity. Together with geroderma osteodysplasticum and arterial tortuosity syndrome, which show phenotypic overlap with CL, eleven CL-related genes have been identified to date, which encode proteins within 3 groups. Elastin, fibulin-4, fibulin-5 and and latent transforming growth factor-beta-binding protein 4 are secreted proteins which form elastic fibers and are involved in the sequestration and subsequent activation of transforming growth factor-beta (TGFβ). Proteins within the second group, localized to the secretory pathway, perform transport and membrane trafficking functions necessary for the modification and secretion of elastic fiber components. Key proteins include a subunit of the vacuolar-type proton pump, which ensures the efficient secretion of tropoelastin, the precursor or elastin. A copper transporter is required for the activity of lysyl oxidases, which crosslink collagen and elastin. A Rab6-interacting goglin recruits kinesin motors to Golgi-vesicles facilitating the transport from the Golgi to the plasma membrane. The Rab and Ras interactor 2 regulates the activity of Rab5, a small guanosine triphosphatase essential for the endocytosis of various cell surface receptors, including integrins. Proteins of the third group related to CL perform metabolic functions within the mitochondria, inhibiting the accumulation of reactive oxygen species. Two of these proteins catalyze subsequent steps in the conversion of glutamate to proline. The third transports dehydroascorbate into mitochondria. Recent studies on CL-related proteins highlight the intricate connections among membrane trafficking, metabolism, extracellular matrix assembly, and TGFβ signaling.

Autosomal‐dominant cutis laxa resulting from an intronic mutation in ELN

“…The mechanism of action of this mutation seems to involve a dominant negative effect (3,4) as attested by the abnormal structure of the elastic fibre network in the skin of the patient, reminiscent of a previous case (7). Of note, the patient was found to express an alternatively spliced ELN isoform, lacking exon 31.…”

“…Autosomal-dominant cutis laxa (ADCL, MIM #123700) is a clinically variable form of CL, featuring generalized lax skin folds and sagging skin with occasional internal organ involvement, including aortic and pulmonary abnormalities (2)(3)(4). The large majority of patients with ADCL carry heterozygous mutations in ELN, encoding elastin, with most cases arising from frameshift mutations at the 3 0 -end of the ELN transcript that encodes a sequence important for fibre assembly and elastin function (5)(6)(7)(8).…”

“…Recent evidence indicates that IL-36 cytokines (IL-36a, IL-36b and IL-36c) also play an important role in psoriasis (3,4). These cytokines bind to IL-36 receptor (IL-36R) and activate NF-jB (s1).…”

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

“…Cutis laxa is a heterogeneous group of disorders characterized by redundant and inelastic skin with variable internal organ involvement (1,2). Fibulin-4, fibulin-5, and LTBP4 (latent TGF-␤ binding protein 4) are three elastic fiber components that underlie autosomal recessive cutis laxa (ARCL) 2 type 1B (OMIM #614437), 1A (OMIM #219100), and 1C (OMIM #613177), respectively.…”

“…Absence of any of the three proteins impairs elastic fiber formation during organogenesis. ARCL 1B, caused by mutations in the gene encoding fibulin-4 (EFEMP2/ FBLN4, hereafter referred to as FBLN4), is a very severe and often lethal disease caused by cardiopulmonary failure (1,2). The typical clinical manifestations are loose skin, aortic aneurysm, arterial tortuosity, and pulmonary emphysema.…”