An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa

Abstract

Elastin is the protein responsible for the characteristic elastic properties of many tissues including the skin, lungs and large blood vessels. Loss-of-function mutations in the elastin gene are known to cause the heart defect supravalvular aortic stenosis (SVAS). We and others have identified deletions, nonsense mutations and splice site mutations in SVAS patients that abolish the function of one elastin gene. We have now identified an elastin mutation in a patient with a completely different phenotype, the rare autosomal dominant condition cutis laxa. A frameshift mutation in exon 32 of the elastin gene is predicted to replace 37 amino acids at the C-terminus of elastin by a novel sequence of 62 amino acids. mRNA and immunoprecipitation studies show that the mutant allele is expressed. Electron microscopy of skin sections shows abnormal branching and fragmentation in the amorphous elastin component, and immunocytochemistry shows reduced elastin deposition in the elastic fibres and fewer microfibrils in the dermis. These findings suggest that the mutant tropoelastin protein is synthesized, secreted and incorporated into the elastic matrix, where it alters the architecture of elastic fibres. Interference with cross-linking would reduce elastic recoil in affected tissues and explain the cutis laxa phenotype.

Elastin (ELN) gene point mutation in patients with inguinal hernia

“…Mutations in the elastin (ELN) gene may be responsible for disorders of the elastic fiber system because they have been observed in cases of supravalvular aortic stenosis and autosomal dominant cutis laxa, individuals with either of these conditions may show smooth and soft skin, hernias, gastrointestinal diverticula and genital prolapse (Ewart et al, 1994;Li et al, 1997;Meng et al, 1998;Tassabehji et al, 1998). These reports and our previous studies plus the findings by Pans et al (2001) that there were biomechanical and structural changes in the fascia transversalis from both the herniated and the non-herniated sides of individual hernia sufferers suggests that hernias may represent a localized somatic expression of a generalized alteration in collagen and elastic fibers, possibly linked to as yet unknown genetic factors.…”

“…It appears that the accumulation of damaged elastic fibers which occurs in the fascia transversalis of elderly people and patients with inguinal hernia may be a consequence of mutations in ELN gene. Tassabehji et al (1998) detected a frameshift mutation in exon 32 of the ELN gene of a patient affected by dominant autosomal cutis laxa, this mutation produced a defective tropoelastin protein which altered the architecture of elastic fibers and produced skin with a prematurely aged appearance.…”

“…Some studies have shown reduced amounts of collagen in the fascia transversalis of patients with direct inguinal hernia compared to those with indirect hernia, suggesting that the development of some hernias might be influenced by disturbances in collagen metabolism (Pans et al, 2001;Rodrigues Jr et al, 2002). Taken together, these results indicate that there is a loss of tensile resistance and elasticity in the fascia transversalis tissue which may explain the high incidence of inguinal hernia after the fifth decade of life.Mutations in the elastin (ELN) gene may be responsible for disorders of the elastic fiber system because they have been observed in cases of supravalvular aortic stenosis and autosomal dominant cutis laxa, individuals with either of these conditions may show smooth and soft skin, hernias, gastrointestinal diverticula and genital prolapse (Ewart et al, 1994;Li et al, 1997;Meng et al, 1998;Tassabehji et al, 1998). These reports and our previous studies plus the findings by Pans et al (2001) that there were biomechanical and structural changes in the fascia transversalis from both the herniated and the non-herniated sides of individual hernia sufferers suggests that hernias may represent a localized somatic expression of a generalized alteration in collagen and elastic fibers, possibly linked to as yet unknown genetic factors.…”

Elastin: mutational spectrum in supravalvular aortic stenosis

“…Abnormalities of elastic fibres, which are composed mainly of amorphous elastic (95%) and microfibrils, cause several cardiovascular, connective tissue and skin disorders, including Marfan syndrome, supravalvular aortic stenosis (SVAS) and Cutis Laxa. [1][2][3][4] SVAS is an obstructive vascular lesion with an incidence of 1/20 000 births, described in 1842 by Chevers,5 and was the first disorder to be associated with the elastin gene (ELN). The aortic narrowing can occur as a discrete hourglass deformity or as diffuse aortic hypoplasia and may be associated with other vascular lesions, the association with pulmonary arterial stenoses being well recognised.…”

Refinement of the genomic structure of STX1A and mutation analysis in nondeletion Williams syndrome patients

“…WS is a contiguous gene deletion disorder involving at least 17 genes within a commonly deleted region on chromosome 7q11.23. Hemizygosity for elastin has been shown to be responsible for several features of WS, such as supravalvular aortic stenosis and possibly the connective tissue abnormalities [Ewart et al, 1993;Li et al, 1997;Tassabehji et al, 1997;Tassabehji et al, 1998], but no other gene has been definitely implicated in the WS phenotype.…”