Table 2:
Osteogenesis imperfecta.
| Type | OMIM phenotype | Defective gene | Protein | OMIM | Locus gene | Inheritance, associated features |
|---|---|---|---|---|---|---|
| Defects in procollagen/collagen synthesis and processing | ||||||
| I | 166200 | COL1A1 | Collagen, type I, alpha −1 | 120150 | 17q21.33 | AD, variant structure of the collagen propeptide, modifications, helical formation; multiple bone fractures with minimal trauma, blue sclerae, normal teeth, near normal height |
| II | 166219 | COL1A1, COL1A2 | Collagen, type I, alpha-2 | 120160 | 7q21.3 | AD, in utero and perinatal fractures, death often in perinatal period |
| III | 259420 | COL1A1, COL1A2 | AD, fading blue sclerae, progressive deformities in late childhood, dentinogenesis imperfecta of primary teeth | |||
| IV | 166220 | COL1A1, COL1A2 | AD, Prepubertal bone fragility nearly white sclerae | |||
| XIII | 614856 | BMP1 | Bone morphogenetic protein | 112264 | 8p21.3 | AR, deficiency of C-propeptidase, 1 severe skeletal deformity |
| XXII | 618788 | CCDC134 | Coiled-coil domain-containing protein 134 | 618788 | 22q13.2 | AR, impacts transcription, intracellular signal transduction, decreases expression of COL1A1 |
| Ehlers-Danlos syndrome/Osteogenesis imperfecta | ||||||
| 619115 | COL1A1 | Collagen, type I, alpha 1 | 120150 | 17q21.33 | AD, Bone fragility with joint hyperextensibility | |
| Defects in collagen modification | ||||||
| VII | 610682 | CRTAP | Cartilage-associated protein | 605497 | 3p22.3 | AR, scafolding protein forming complex with prolyl 3-hydroxylase; severe to lethal |
| VIII | 610915 | P3H1 | Prolyl 3-hydroxylase 1 | 610339 | 1p34.2 | AR, Hydroxylates carbon 3 of proline at position 986 of collagen type 1 alpha 1- essential for collagen cross-linking, severe to lethal |
| IX | 259440 | PPIB | Peptidyl-prolyl isomerase B | 12384 | 15q22.31 | AR, catalyzes isomerization of proline, an amino acid essential for synthesis of bone collagen, gray sclerae, bowing of femur, tibia |
| XIV | 615066 | TMEM38B | Transmembrane protein 38B | 611236 | 9q31.2 | AR, monovalent cation channel in endoplasmic reticulum important for intracellular collagen movement, normal to blue sclerae, severe |
| Abnormalities of collagen folding and cross-linking | ||||||
| X | 613848 | SERPINH1 | Serpin peptidase inhibitor | 600943 | 11q13.5 | AR, collagen binding protein, also termed heat shock protein 47; monitors rate of movement of type I procollagen from endoplasmic reticulum to the Golgi apparatus, severe, dentinogenesis imperfecta |
| XI | 610968 | FKBP10 | FK506-binding protein | 607063 | 17q21.2 | AR, collagen chaperone assisting in collagen folding; interacts with SERPINH1, joint contractures, Bruck syndrome #1 |
| 259450 | FKBP10 | AR, bone fragility, congenital contractures, pterygia, Bruck syndrome #2 | ||||
| NAa | 609220 | PLOD2 | Procollagen-lysine, 2-oxoglutarate, 5-dioxygenase 2 | 601865 | 3q24 | AR, lysyl hydroxylase 2 – enzyme that hydroxylates lysine residues in telopeptides of domains enabling cross-linking of collagen strands; associated with bone fragility, joint contractures, pterygia Bruck syndrome #2/osteogenesis imperfecta |
| XXI | 619131 | KDELR2 | KDEL endoplasmic reticulum protein retention receptor 2 | 609024 | 7p22.1 | AR, receptor that cycles between the endoplasmic reticulum and Golgi apparatus transferring proteins with a carboxyl-terminal sequence of Lys-Asp-Glu-Leu (KDEL) |
| Abnormalities of osteoblast differentiation and function | ||||||
| XII | 613849 | SP7 | Transcription factor SP7 | 606633 | 12q13.13 | AR, controls osteoblastic bone formation, moderately severe |
| XV | 615220 | WNT1 | Wingless-type MMTV integrative site family, member 1 | 164820 | 12q13.12 | AR/AD, stimulates osteoblast differentiation, severe skeletal deformities, neurological defects |
| XVI | 616229 | CREB3L1 | cAMP Response element binding protein 3-like 1 | 616215 | 11 p11.2 | AR, affects the unfolded protein response resulting in alteration of protein processing in the osteoblast, developmental delay |
| XVII | 616507 | SPARC | Secreted protein, acidic, cysteine-rich | 182120 | 5q33.1 | AR, glycoprotein that binds to type 1 collagen in the extracellular matrix, pectus deformity |
| XVIII | 617952 | TENT5A | Terminal nucleotidyl-transferase 5A | 611357 | 6q14.1 | AR, increases expression of COL1A1 and COL1A2, joint contractures |
| XIX | 301014 | MBTPS2 | Membrane-bound transcription factor protease, site 2 | 300294 | Xp22.12 | XLR, acts within Golgi apparatus to release membrane-bound proteins |
| XX | 618644 | MSED | Mesoderm development LRP chaperone LRP 5 and 6 | 607783 | 15q25.1 | AR, essential for osteoblast differentiation as a chaperone for defects in mineralization of bone |
| V | 610967 | IFITM5 | Interferon-induced transmembrane protein 5 | 614757 | 11 p15.5 | AD, ossification of forearm interosseous membrane, hyperplastic callus formation |
| VIa | IFITM5 | Fish-scale pattern in lamellar bone, increased osteoid | ||||
| VI | 613982 | SERPINF1 | Serpin peptidase inhibitor, Clade F, Member 1 | 172860 | 17p13.3 | AR, fish-scale pattern in lamellar bone, increased osteoid |
| NAa - Cole-Carpenter syndrome type 1 | 112240 | P4HB | Prolyl 4-hydroxylase, beta subunit | 176790 | 17q25.3 | AD, bone fragility, craniosynostosis; hydroxylates prolyl residues in preprocollagen |
| NAa - Cole-Carpenter syndrome type 2 | 616294 | SEC24D | SEC24-related gene family, member D | 607186 | 17q25.3 | AR, bone fragility, craniosynostosis; mediates protein transport from endoplasmic reticulum |
a
NA, not assigned; AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive. [Modified from 41. Jovanovic M, Guterman-Ram G, Marini JC. Osteogenesis imperfecta: Mechanisms and signaling pathways connecting classical and rare OI types. Endocrine Rev 2022;43:61–90. doi:10.1210/endrev/bnab017. 43. Etich J, Leβmeier L, Rehberg M, et al. Osteogenesis imperfecta – pathophysiology and therapeutic options. Mol Cell Pediatr 2020;7:9. https://doi.org/10.1186/s40348-020-00101-9].