A missense mutation in fibulin-5, encoding a widely expressed constituent of the extracellular matrix that has an essential role in elastic fibre assembly and has been shown to cause cutis laxa, was detected as the only novel non-synonymous sequence variant within the disease interval.
Missense mutations in fibulin 5 cause the elastin disorder cutis laxa and have been associated with age-related macular degeneration, a leading cause of blindness.
The 'Vitamin K deficit and elastolysis theory' posits that elastin degradation causes a rise in the vitamin K deficit and implies that vitamin K supplementation could be preventing elastin degradation.
FBLN5 mutations are associated with two distinct human diseases, age-related macular degeneration (AMD) and cutis laxa (CL), but the biochemical basis for the pathogenic effects of these mutations is poorly understood.
To investigate the molecular mechanisms leading to cutis laxa in vivo, we generated transgenic mice by pronuclear injection of minigenes encoding normal human tropoelastin (WT) or tropoelastin with a cutis laxa mutation (CL).
Molecular study of the fibulin-5 (FBLN5) gene in a large consanguineous Turkish family with four patients affected by AR cutis laxa type I demonstrated the presence of a homozygous missense mutation (T998C) in the FBLN5 gene resulting in a serine-to-proline (S227P) substitution in the fourth calcium-binding epidermal growth factor-like domain of fibulin-5 protein.
This study investigates the expression profiles of genes responsible for the elastolysis in the dissected human aorta, especially those coding fibulin-1, matrix metalloproteinase-9 (MMP-9), and elastin.
An autosomal-recessive form of cutis laxa is due to homozygous elastin mutations, and the phenotype may be modified by a heterozygous fibulin 5 polymorphism.
Cutis laxa is an uncommon connective tissue disorder affecting the elastin fibers leading to lax and pendulous skin and in generalized form can present with systemic involvement.
This article is the fourth report of autosomal dominant cutis laxa to appear in the literature in which a mutation in the elastin gene has been correlated with the disease.
The abnormal synthetic repertoire of these morphologically abnormal smooth muscle cells in early vascular lesions included elastin, among other matrix elements, and matrix metalloproteinase 9, a known mediator of elastolysis.
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.
The results demonstrate that a heterozygous mutation in fibulin-5 can cause cutis laxa and also suggest that fibulin-5 and elastin gene mutations are not the exclusive cause of the disease.
The results of the present study indicate that PKCε, activated by DCP-LA, increases elastin and fibulin-5/DANCE in the extracellular space of cultured fibroblasts by the mechanism independent of transcriptional and translational modulation or inhibition of elastolysis.