title: Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation.
abstract: OBJECTIVE
  Osteogenesis imperfecta or 'brittle bone disease' has mainly been considered a bone disorder caused by collagen mutations. Within the last decade, however, a surge of genetic discoveries has created a new paradigm for osteogenesis imperfecta as a collagen-related disorder, where most cases are due to autosomal dominant type I collagen defects, while rare, mostly recessive, forms are due to defects in genes whose protein products interact with collagen protein. This review is both timely and relevant in outlining the genesis, development, and future of this paradigm shift in the understanding of osteogenesis imperfecta.
  
  
  RESULTS
  Bone-restricted interferon-induced transmembrane (IFITM)-like protein (BRIL) and pigment epithelium-derived factor (PEDF) defects cause types V and VI osteogenesis imperfecta via defective bone mineralization, while defects in cartilage-associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1), and cyclophilin B (CYPB) cause types VII-IX osteogenesis imperfecta via defective collagen post-translational modification. Heat shock protein 47 (HSP47) and FK506-binding protein-65 (FKBP65) defects cause types X and XI osteogenesis imperfecta via aberrant collagen crosslinking, folding, and chaperoning, while defects in SP7 transcription factor, wingless-type MMTV integration site family member 1 (WNT1), trimeric intracellular cation channel type b (TRIC-B), and old astrocyte specifically induced substance (OASIS) disrupt osteoblast development. Finally, absence of the type I collagen C-propeptidase bone morphogenetic protein 1 (BMP1) causes type XII osteogenesis imperfecta due to altered collagen maturation/processing.
  
  
  CONCLUSIONS
  Identification of these multiple causative defects has provided crucial information for accurate genetic counseling, inspired a recently proposed functional grouping of osteogenesis imperfecta types by shared mechanism to simplify current nosology, and has prodded investigations into common pathways in osteogenesis imperfecta. Such investigations could yield critical information on cellular and bone tissue mechanisms and translate to new mechanistic insight into clinical therapies for patients.
authors.affiliation: Bone and Extracellular Matrix Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.forename: Adi
authors.initials: A
authors.lastname: Reich
authors.forename: Simone M
authors.initials: SM
authors.lastname: Smith
mesh_terms: D000943:Antigens, Differentiation / Q000235:genetics; D055395:Bone Morphogenetic Protein 1 / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D021983:Cyclophilins / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D050958:HSP47 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D018832:Molecular Chaperones; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010012:Osteogenesis / Q000235:genetics; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology*; D064828:Prolyl Hydroxylases; D011509:Proteoglycans / Q000235:genetics; D015843:Serpins / Q000235:genetics; D000076182:Sp7 Transcription Factor; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D051155:Wnt1 Protein / Q000235:genetics; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000943:Antigens, Differentiation; D055395:Bone Morphogenetic Protein 1; D017362:Cyclic AMP Response Element-Binding Protein; D021983:Cyclophilins; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D050958:HSP47 Heat-Shock Proteins; D007473:Ion Channels; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D064828:Prolyl Hydroxylases; D011509:Proteoglycans; D015843:Serpins; D000076182:Sp7 Transcription Factor; D022021:Tacrolimus Binding Proteins; D014157:Transcription Factors; D051155:Wnt1 Protein; D000099174:Pigment Epithelium-Derived Factor; C485618:CREB3L1 protein, human; C108053:CRTAP protein, human; C575746:IFITM5 protein, human; C494660:SERPINH1 protein, human; C478163:SP7 protein, human; C578840:TMEM38B protein, human; C495247:WNT1 protein, human; C062010:leu-13 antigen; C081786:cyclophilin B; C485657:P3H1 protein, human; C525705:BMP1 protein, human; C110054:FKBP10 protein, human