Can OI Result From Mutation In Genes Other Than Those For Type I Collagen?

Michel van der Rest
Institut de Biologie Structurale (CEA-CNRS), 41 rue Jules Horowitz, 38027, Grenoble cedex 1, FRANCE

Over the last 20 years, the implication of mutations occurring in type I collagen genes in the pathogenesis of Osteogenesis Imperfecta (OI) has been demonstrated by a number of studies performed in all OI types of the classification of Sillence. Several techniques have been used to identify mutations in COL1A1 and COL1A2, such as denaturing gradient gel electrophoresis (DGGE), single strand conformation polymorphism (SSCP), or straight sequencing, as well as protein based techniques. However it is the experience of all laboratories that have performed systematic collagen gene analysis for mutation identification in OI that, whatever the technique used, a collagen mutation is not detected or identified in a significant proportion of the cases. This can be interpreted as technical failure to identify subtle mutations. This is indeed the case as all techniques are not equally sensitive to detect all types of mutations. Failure to detect an OI mutation in collagen gene may also be due to the fact that the mutant locus is not COL1A1 or COL1A2.

In a few OI cases, genetic linkage analysis has definitely excluded COL1A1 or COL1A2 as the mutant locus. This has been shown in cases of recessive inheritance in a south-African family (Wallis et al., 1993, J. Med. Genet. 30:492-6) and in a Native American community (see abstract by Travers et al., P-44). The clinical phenotype in these families is that of OI, except of course for the recessive inheritance. Obviously, linkage analysis cannot be performed for sporadic cases and it is therefore likely that an unknown but small percentage of those cases may be due to recessive mutations in genes other than those for type I collagen.

It has long been known that the inactivation of one allele in the COL1A1 locus is sufficient to produce type I OI. One has therefore to consider the possibility that mutations in other genes that would directly or indirectly reduce collagen gene expression, or levels of collagen mRNA translation, or levels of collagen secretion or deposition in the tissue can result in an OI phenotype. The identification of the gene(s) involved in recessive forms of OI not linked to collagen genes could therefore be of great importance to understand the mechanisms that control collagen synthesis and deposition in bone.

Reference: Proceedings of the 7th International Conference on Osteogenesis Imperfecta. Montreal, Canada, 1999.