At a time when the debate regarding how a state of acute bone and soft-tissue inflammation could be limited in time and space and yet be transmitted as an autosomal dominant trait with incomplete penetrance is at a virtual standstill comes the surprising finding reported in this issue of the JCI
that ICH is closely associated with a mutation in COL1A1
, the gene encoding the α1 chain of type I collagen (6
). The careful and elegant work of Gensure et al. has established a strong linkage between the ICH phenotype and the COL1A1
locus on chromosome 17q21 in 3 discrete pedigrees from Australia and Canada with an autosomal dominant form of ICH. More importantly, despite the fact that the families were geographically dispersed and unrelated, it was found that all affected individuals were heterozygous for the identical mutation, a substitution of Arg by Cys at position 836 (R836C), within the helical domain of the α1 chain of type I collagen. The linkage and sequencing data are solid and convincing and represent a major step forward in the understanding of the pathology of an elusive disease.
One has to now try and understand how a point mutation in a widely distributed structural protein can initiate the cascade of inflammatory events that lead to ICH. Type I collagen, the most abundant protein present within bone, is also present in periosteum, ligaments, dermis, and tendon. It is made of a long, continuous triple helix that assembles in highly organized collagen fibrils. The fibrils have high tensile strength, which is critical for the function of bone and other tissues (7
). Glycine occurs at every third residue of the triple-helical domain. Because of its small size, it packs tightly at the center of the helix and confers stability. A mutation affecting a Gly residue will thus have an impact on the conformation of the collagen molecule, its integration in the tissue (bone, skin, and tendon), and the structural qualities of the tissue. This is the case in osteogenesis imperfecta, or brittle bone disease, where most mutations within COL1A1
are glycine substitutions. The severity of the phenotype is determined in part by the pattern of inheritance, the position of the mutation in the α1 chain, and the bulkiness of the replacement residue, as it will variably compromise formation and stability of the helix.
In contrast, the R836C mutation identified by Gensure et al. (6
) in these ICH patients would not be predicted to have such an effect on the collagen molecule. Why and how it would instead stimulate new bone formation through a process of inflammation has yet to be understood. There has been only one other Arg-to-Cys substitution reported in the α1 chain of type I human collagen. R134C is associated with classical Ehlers-Danlos syndrome (EDS), which is characterized by skin hyperelasticity, joint hypermobility, increased tendency to bruise, and abnormal scarring (8
). Some of the clinical features of EDS are actually evident in the families with ICH studied by Gensure et al. (6
), and this makes sense. But the reason why some ICH patients also develop acute bone lesions at a specific age is not clear. The authors hypothesize that periosteum is only loosely attached to the underlying bone structure in infants and that periosteum detachment (perhaps facilitated by the collagen mutation) would be the primum movens
leading to increased bone formation. Such a hypothesis is not entirely consistent with the histologic studies done sequentially in cases of ICH (3
), which clearly indicate that inflammation is the initial event, in agreement with the clinical and PGE-related observations. It is noteworthy that Gensure et al. found that 79% of the individuals studied who were heterozygous for the COL1A1
mutation had an episode of cortical hyperostosis, while 21% of the subjects carrying the R836C substitution do not develop disease, which confirms the clinically observed reduced penetrance at the molecular level. Many unresolved questions regarding the pathology of this disease may have to wait for the engineering of an appropriate mouse model.
In conclusion, by showing convincingly that Caffey disease is associated with a COL1A1
missense mutation, Gensure et al. (6
) have once again demonstrated the power of linkage analysis. They have lifted the lid of a black box, but what is inside the box remains to be discovered.