Marfan syndrome: abnormal alpha 2 chain in type I collagen.

Abstract

Cells in culture from a woman with a variety of the Marfan syndrome produce two species ofthe a2 chains of type I collagen. One a2 chain appears normal; the abnormal chain has a higher apparent molecular weight than normal and migrates more slowly during electrophoresis in sodium dodecyl sulfate/ polyacrylamide gels. A similar change in electrophoretic behavior is seen in the preproa2 chain and the pNa2 chain (which contains the amino-terminal extension). Asymmetric cleavage of the pepsin-treated procollagens with a fibroblast collagenase locates the abnormal segment amino terminal to the cleavage site, and analysis of cyanogen bromide peptides of collagenase cleavage peptides and of whole collagens indicates that the abnormal segment is in either the a2CB3 peptide or the short segment of c2CB5 amino terminal to the collagenase site ofthe altered a2 chain. The higher apparent molecular weight is consistent with the insertion of a small peptide fragment of approximately 20 amino acids. This alteration in chain size has marked effects on crosslinking because collagen from the patient's skin was 5-10 times more extractable in nondenaturing solvents than that from control skins. Although the abnormal chain was not found in several other individuals with the Marfan syndrome, these findings suggest that the phenotype may be the expression ofa variety ofprimary structure alterations in the chains of type I collagen that interfere with normal crosslink formation.The Marfan syndrome (1-4) is a group of inherited connective tissue disorders that share certain clinical features: severe cardiovascular abnormalities (valvular heart disease and aortic dissection), skeletal alterations (arachnodactyly, pectus deformities, and kyphoscoliosis), and ocular lens dislocation. Despite considerable clinical interest (1) and research activity (3, 4), a clear understanding of the syndrome at the biochemical level has not emerged. Investigations ofglycosaminoglycan synthesis (5-7) and of collagen metabolism (8-13) have suggested that alterations in these macromolecules may be important in the pathogenesis of the syndrome. Dermal fibroblasts from some patients with the Marfan syndrome have been shown to have an increased rate of synthesis ofhyaluronic acid (5, 6), and cellfree systems from these cells also synthesize hyaluronic acid at a higher than normal rate (7). It is not clear, however, that this is the primary disorder rather than a secondary change. Similarly, it is not clear that increased extractability ofcollagen from tissues or of that synthesized by cultured cells reflects the primary biochemical disturbance.Recently Siegel and Chang (11) MATERIALS AND METHODS Clinical Summary. The patient, a 39-year-old woman, was the only affected child of three in the family; both parents were unaffected. She was noted to have equinovarus deformities of both feet at birth; arachnodactyly was first noted at age 9; lumbar scoliosis became apparent and a heart murmur was heard at age 10. Because ofpain and progressive deformity, the...

Restriction fragment length polymorphism associated with the pro alpha 2(I) gene of human type I procollagen. Application to a family with an autosomal dominant form of osteogenesis imperfecta.

“…The data developed here rigorously confirm previous indications that the proa2(I) gene is found in a single copy in the human haploid genome (11,25,26). All the fragments detected with the genomic probe were accounted for by the linear map developed from overlapping phage clones of the human proa2(I) gene (19).…”

Abnormal alpha 2-chain in type I collagen from a patient with a form of osteogenesis imperfecta.

“…Whether this is the result of decreased synthesis of proa2(I) or production of a proa2(I) that does not assemble into type I procollagen molecules is not yet clear (Byers, David, and Hunter, unpublished observation). The biochemical, histologic, and clinical findings in these patients suggest that the a2(I)-chain is important for normal bone structure and that some, but not all (41), alterations in its synthesis and structure may result in abnormal bone mineralization.…”

Marfan syndrome. Demonstration of abnormal elastin in aorta.

“…Also, in one isolated case, an abnormality in the a2 (I)-chain of type I collagen has been reported (9,10). Histopathologic and ultrastructural observations have indicated, however, that the major pathologic feature of the aorta in Marfan syndrome resides in the elastic tissues (11) tery and the descending thoracic and abdominal aorta were revealed a month later.…”