Abstract
For 40 years the pathogenesis of the group of brittle bone disorders collectively named osteogenesis imperfect (OI) has been ascribed to mutations in type I collagen. Recent discoveries in matrix biology have transformed our perspectives on the role of mutations in the α(1)- and α(2)-chains of type I collagen (COLIA1, COLIA2), their post-translational modifications, trafficking and matrix interactions. Furthermore progress in gene discovery has identified 22 genes including the 2 COLI genes, in which mutations result in at least one OI phenotype. The International Bone Dysplasia Committee has grouped the syndromes arising from mutations in these genes into five OI phenotypes. All 3 modes of inheritance, Autosomal Dominant (4 genes) and Recessive (16 genes), X-linked (2 genes) have been discovered. The gene products of the recessive genes have a variety of functions. Mutations in LEPRE1, CRTAP and PIPB regulate prolyl-3-hydroxylation. A recent study in Crtap(−/−) mice showed upregulation of TGF-β target genes and reduced binding of type 1 collagen to the proteoglycan decorin. A similar pattern of TGFB dysregulation was observed in the tissues of heterozygous Col1a(2)(tm1.1 Mcbr) mice. Mutations in FKBP10, SERPINF1 (HSP10), SERPINH1 affect polypeptide trafficking but have other matrix functions. Mutations in PLOD2 and FKBP10 both have extra-skeletal effects on matrices resulting in joint contractures. Mineralisation and osteoclast function are affected by mutations in LRP5, SP7, TMEM38B, WNT1, IFITM5 and CREB3L1 (OASIS), SPARC as do hemizygous mutations in the X-linked gene PLS3. A role for the unfolded protein response (UPR) is observed in the pathogenesis of OI resulting from mutation in CREB3L1. There is some evidence that the frequency of the varying types of OI may vary in and between populations in Asia and the Pacific. OI with Congenital Joint contractures for example is of high frequency in Samoa and Tonga and may well be common in a source community in Asia. Similarly my colleagues have observed a number of families with OI type 5 in the Philippines. This heterogeneity is becoming relevant to management as there is evidence of resistance to bisphosphonate therapy in patients with homozygous mutations in SERPINF1 also known as OI type VI. Non-COL1 related OI is the most prevalent form of OI in some parts of Africa so that it would not be unusual if non-COLI related OI was more prevalent in some communities in the Asia Pacific region. Targeted exome Multiple Parallel sequencing panels are being developed and may be needed in the future to resolve the question of exact diagnosis to facilitate patient care.