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

Abstract

A B S T R A C T Dermal fibroblasts in culture from a woman with a mild to moderate form of osteogenesis imperfecta synthesize two species of the proa2-chain of type I procollagen. One chain is normal. The abnormal chain has a slightly faster mobility than normal during electrophoresis in sodium dodecyl sulfate polyacrylamide gels. Analysis of cyanogen bromide peptides of the proa-chain, the a-chain, and of the mammalian collagenase cleavage products of the proa-and a-chains indicates that the abnormality is confined to the a2(I)CB4 fragment and is consistent with loss of a short triple-helical segment. Type I collagen production was decreased, perhaps because the molecules that contained the abnormal chain were unstable, with a resultant alteration in the ratio of type III to type I collagen secreted into culture medium. Collagen fibrils in bone and skin had a normal periodicity but their diameters were 50% of control; the bone matrix was undermineralized. The structural abnormality in the a2(I)-chain in this patient may affect molecular stability, intermolecular interactions, and collagenmineral relationships that act to decrease the collagen content of tissues and affect the mineralization of bone.

Osteonectin, bone proteoglycan, and phosphophoryn defects in a form of bovine osteogenesis imperfecta.

“…Preliminary data on procollagens synthesized by osteoblasts cultured from bovine OI bone did not show any detectable structural differences from control tissue (unpublished data). This is in contrast to results described for human 01 type II variants (9,(11)(12)(13) and a single case of 01 type I (10) in which defective collagen a chain biosynthesis is well documented (28). Thus, the bovine form of 01 may be similar to other forms of human Ol in which collagen structural gene abnormalities are not well understood (29).…”

“…01 collagens are often present at lower levels than normal, with apparently decreased fibril diameters (4,5) and increased hydroxylysine content (6). Analyses of cultures of skin biopsies from 01 patients have shown a wide range of collagen abnormalities (7,8) with the most severely affected individuals (perinatal lethal form) having structural defects in type I collagen (9)(10)(11)(12)(13). However, the type and extent of the skin collagen abnormalities reported for other forms of OI in surviving individuals do not universally reflect the severity or extent of the underlying bone disease.…”

Single base mutation in the pro alpha 2(I) collagen gene that causes efficient splicing of RNA from exon 27 to exon 29 and synthesis of a shortened but in-frame pro alpha 2(I) chain.

“…Therefore, slippage or misregistration of the tripeptide units in one chain relative to the other two can readily occur (31,32). As a consequence, a mutation that efficiently removes all the codons of one or more exons can generate a shortened proa chain that is incorporated into the triple helix of procollagen (1)(2)(3)(4)(13)(14)(15)(16)(17)(18).…”

“…7-12; C. D. Constantinou, K. B. Nielsen, and D.J.P., unpublished data). A series of additional mutations in probands with osteogenesis imperfecta or Ehlers-Danlos syndrome were observed to cause synthesis of shorter proal or proa2 chains of type I procollagen without any evidence as to whether the mutations were partial gene deletions or RNA splicing mutations (13)(14)(15)(16)(17).…”

Mutations in collagen genes. Consequences for rare and common diseases.

“…The effect of the two mutations was a lethal event, but the reasons for the lethality was not entirely apparent. In another variant of osteogenesis imperfecta, a deletion in the protein of -20 amino acids close to the amino terminus of the a2(I) chain produced a moderately severe form of osteogenesis imperfecta (23). In two variants of osteogenesis imperfecta (24,25), an amino acid substitution was found that introduced a new cysteine residue into the al(I) chain, a chain which normally does not contain cysteine.…”