Homozygous Missense Mutation in Fibulin-5 in an Iranian Autosomal Recessive Cutis Laxa Pedigree and Associated Haplotype

Abstract

Cutis laxa is a rare group of inherited and acquired disorders characterized by loose and redundant skin with reduced elasticity. Mutations in the elastin coding gene have been shown to cause autosomal dominant cutis laxa in three families. A homozygous mutation in the fibulin-5 coding gene was discovered in a Turkish pedigree showing recessive inheritance, and a different mutation in this gene was found in the heterozygous state in a sporadic case of the disease. Here, we report the third case of a mutation in the fibulin-5 coding gene in a recessive Iranian cutis laxa pedigree. The mutation is the same as previously reported in the Turkish pedigree, further confirming that it is causative of disease. A haplotype consisting of seven intragenic sequence variations common to both pedigrees is described for the mutation-carrying fibulin-5 allele.

Molecular Analysis of Fibulin-5 Function during De Novo Synthesis of Elastic Fibers

“…Fibulin-1, -2, -4, and -5 colocalize with elastic fibers and bind tropoelastin (19,27,36), whereas the elastic fiber binding properties of fibulin-3 and -6 have not been determined. In addition to tropoelastin, fibulin-5 was shown to bind N-terminal fragments of fibrillin-1 without interfering with either the homophilic interaction of fibrillin-1 or the heterotypic interaction of fibrillin-1 with tropoelastin (9). Binding of fibulin-5 to the integrin receptors ␣V␤3, ␣V␤5, and ␣9␤1 in adhesion assays (22,23) suggests that fibulin-5 may serve to anchor tropoelastin to surrounding cells during assembly and/or final organization of functional elastic fibers.…”

Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debré type

“…In the pulmonary emphysema subtype, homozygous mutations of EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) and both homozygous and heterozygous mutations of Fibulin-5 (FBLN5) have been reported, the latter blurring the distinction between autosomal dominant and recessive forms. [1][2][3][4] Mutations in the elastin (ELN) gene have been reported in six families with autosomal dominant cutis laxa associated with variable aortic aneurisms or pulmonary emphysema. [5][6][7][8][9] Recently, a Dutch group described N-and O-linked glycosylation defects in three patients with autosomal recessive cutis laxa and developmental delay.…”

Defining the phenotype in an autosomal recessive cutis laxa syndrome with a combined congenital defect of glycosylation

“…This type of cutis laxa can be readily distinguished from ARCL type I, which is commonly associated with severe cardiopulmonary lesions, including infantile emphysema and supravalvular aortic stenosis, and is caused by mutations in the FBLN5 gene. 4,19 There are many overlapping features regarding the phenotype in ARCL type III (MIM 219150) and our patients. Although both groups show a late closure of the anterior fontanel, the facial features are quite (Table 3).…”