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Osteogenesis Imperfecta (COL1A1, COL1A2)
radiographic.3 The classification system most widely used today is based on clinical. . prolines and lysines in the alpha chains are chemically modified by addition of hydroxyl or sugar groups. can lead to bone deformity. An earlier grouping system distinguished between OI Congenita. and histological information4-7 and distinguishes between type I (mild). since only glycine. Introduction Osteogenesis imperfecta (OI). the smallest of all amino acids. and types IV-VII (moderately severe and moderately deforming). Two alpha1 helices and one alpha2 helix then wind around each other to form a right-handed triple helix. At least 90% of all cases of OI.000 children under the age of three and is thus much more common than OI.Frequently Used Abbreviation: OI: osteogenesis imperfecta. in its more severe forms. Completed triplehelices are secreted from the cells and spontaneously assemble into collagen fibrils. Both the alpha1 chain encoded by COL1A1 and the alpha2 chain encoded by COL1A2 are built from 338 uninterrupted repeats of the amino acid sequence Glycine-X-Y. Role of Type I Collagen in Osteogenesis Type I collagen creates layers of fibrils in the extracellular matrix of bone. since preventive and therapeutic measures. but require a skin biopsy and typically take two months. also known as Brittle Bone Disease. the alpha chains assume a left-handed helical conformation.000 births. giving bone its tensile strength and forming a template for the deposition of inorganic minerals. These modifications are believed to play a role in triple helix stabilization. This delay in diagnosis can be problematic. Prior to and simultaneously with triple helix formation. type III (severe and deforming). which occurs at an estimated frequency of 1:10. Triple helix formation starts at the C-termini of the alpha chains and proceeds toward the N-termini in a zipper-like fashion. since non-traumatic fractures in infants can be misinterpreted as a sign of child abuse. or even death. but in as little as two to three weeks and based on a single blood draw. disability. Presence of a glycine in every third position is critical for triple helix formation.1 Early diagnosis of OI is important. Due to the regular pattern of prolines and hydroxyprolines.2 Genetic testing for OI-associated loss-of-function mutations in COL1A1 and COL1A2 can diagnose OI with a sensitivity similar to that of biochemical testing. and OI Tarda. type II (perinatally lethal). However. the milder (and more common) forms of OI (also known as OI Tarda) may be difficult to diagnose in infants. which can range from perinatal death to premature osteoporosis without any fractures. including bisphosphonate treatment. Type I collagen owes its ability to form fibrils to its very specific amino acid sequence. Types and Causes of OI Classification of OI into different types is mostly based on severity of the phenotype. with fractures occurring in utero or at birth. Biochemical studies on type I collagen from cultured skin cells can confirm most cases of OI. are believed to be associated with autosomal dominant loss-of-function mutations in either of the two genes coding for type I collagen. Child abuse has been reported in 24 out of 10. can minimize the number of bone fractures and reduce the extent of bone deformity. and may force a separation of infants and parents until a diagnosis of OI can be confirmed. is characterized by frequent bone fractures after little or no trauma and. COL1A1 or COL1A2. with the first fracture occurring after birth. where X is often proline and Y is often hydroxyproline. fits into the confined space in the center of the triple helix.
since co-polymerization of normal and mutated triple helices into collagen fibrils results in the formation of a poorly organized protein matrix. However.5-7 Null Mutations in Type I Collagen Genes Many null mutations lead to translation of a C-terminally truncated alpha chain. Therefore.. as is the collagen fibril containing the mutant triple helix. Other null mutations may decrease messenger RNA stability or may affect transcription or processing of messenger RNA. helix formation is temporarily halted. Dominant Negative Mutations in Type I Collagen Genes The majority (85%) of dominant negative mutations in type I collagen genes are due to replacements of one of the obligatory glycines in the alpha chains by a bigger amino acid. which no longer contains the C-terminal nucleation site for triple helix formation. i. Typically.8 Types V-VII OI Types V-VII are caused by mutations in other. Since the bigger amino acid does not easily fit into the interior space of the triple helix. the mutated gene does not give rise to an alpha chain that can be assembled into a triple helix. these mutations are null mutations.Types and Causes of OI Type of OI I II III IV V VI VII Bone Fragility mild lethal severe moderate moderate moderate moderate Bone Deformity none lethal severe moderate moderate moderate moderate Mutation in type I collagen type I collagen type I collagen type I collagen unknown unknown unknown Effect of Mutation null mutation dominant negative dominant negative dominant negative unknown unknown unknown Inheritance Pattern autosomal dominant autosomal dominant autosomal dominant* autosomal dominant autosomal dominant unknown autosomal recessive * Autosomal recessive in rare cases Type I OI Type I OI is the mildest type of OI and is caused by mutations in COL1A1 or COL1A2. This pause in triple helix formation leads to over-modification of amino acids N-terminal to the mutation. the mutations associated with types II-IV OI reduce the quality of the type I collagen in bone. as yet unidentified genes. These mutations have a dominant negative effect. affecting mineral deposition into the bone and reducing its tensile strength.e. the triple helix containing the mutant alpha chain is structurally compromised. . Both the distortion in the triple helix and the over-modification of the alpha chains are believed to affect the structure and stability of the triple helix and the collagen fibrils. Types II-IV OI Types II-IV are caused by mutations in COL1A1 or COL1A2 that lead to synthesis of a mutated alpha chain still able to form a triple helix. null mutations reduce the overall quantity of type I collagen in bone and cause mild OI due to haploinsufficiency. Thus.
radiological. Type IV OI may be more severe than type I but is usually milder than type III. type I OI is accompanied by dentinogenesis imperfecta (DI). since bones are not only highly fragile. OI is also associated with premature osteoporosis. Fractures are generally more frequent before puberty and beyond middle age. Bones are fragile and may break after minimal trauma but are usually not deformed. OI has been classified into seven types based on clinical. and increased bruising. individuals with type III OI often become wheelchair bound. a disproportionately wide arm span.1 Patients in this group typically have white sclera and do not suffer from DI. and a scleral hue may be present. often starting in utero. Without aggressive intervention.10. and infants are either stillborn or unlikely to survive infancy. Rarely. mild joint hypermobility. Defining characteristics for a given type of OI may not always be present or may be shared by different types. since OI presents with an essentially continuous spectrum of severity. Based on histological findings. Severe early hearing loss is common. about 8% of OI type IV have been reclassified into separate categories. Type I OI is the mildest and most common form of OI. and usually remain very short in stature. Subjects are often short of stature and may suffer from DI or hearing loss. By adolescence or early adulthood. Type II OI is the most severe form of OI and accounts for about 5% of all cases of OI. Subjects with type I OI often. but bone deformity is generally mild to moderate. but not always. Defining characteristics are a triangular face and disproportionately short legs. and subjects often attain normal stature. and a disproportionately big cranium. bones are severely deformed. as is DI. which is characterized by discolored and brittle teeth. Type III OI is the most severe form of OI that is compatible with survival past infancy and accounts for about 20% of all cases of OI. about 50% of patients will be affected by functional hearing loss.11 This type of OI is also known as the Progressive Deforming Type. but also tend to become deformed over time due to tension from attached muscles or angulated healing of fractures. the borders between these groupings are blurred. Typical Clinical Presentation of OI Types I through VII Type of OI I II III IV V VI VII Bone Deformity no severe severe moderate moderate Stature normal / very short short short Scleral Hue blue dark grey no no Often Associated With Hearing Loss DI yes / yes no no no / yes yes no . A scleral hue may be present.9 In general. and histological criteria.11 Bone fractures often occur in utero. due to the protective effect of sex hormones on bones.10. have blue sclera. and the same mutations can lead to different types of OI in different individuals. mild to moderate OI is much more common than severe OI. Bone fractures are frequent. types V through VII.Clinical Presentation of OI The main characteristic of OI is bone fragility: Individuals can suffer from tens to hundreds of bone fractures during their lifetimes.4-7 However. Patients with type III OI may experience hundreds of fractures over their lifetime.
Treatment of OI Apart from treatment of fractures as necessary. Most OI-associated mutations in COL1A1 and COL1A2 are autosomal dominant. The more severe forms of OI (types II and III) can usually be confirmed through radiographic examination of the bones and measurements of body proportions. In addition. treatment with bisphosphonates such as pamidronate has been shown to increase bone mass and to decrease bone pain and frequency of fractures. A diagnosis of OI can be confirmed through biochemical analysis of the type I collagen produced by cultured skin fibroblasts from the patient. Recently. especially in infants. such as bracing or surgical insertion of rods along bones. is common in all babies up to 18 months of age. orthopedic intervention may be necessary. and can identify about 90% of all cases of OI. the genes coding for type I collagen.17 About 50% of OI occurs in families without a history for the disease.15 Use of growth hormone to correct OI-associated short stature is also under investigation. Genetic testing requires less time than biochemical testing and detects a similar proportion (about 90%) of all cases of OI. short stature. Therefore. scleral hue. genetic testing detected all cases of type-I-collagen related OI. are not known yet. are believed to be associated with mutations in COL1A1 or COL1A2. Genetic testing can confirm a diagnosis of OI faster than currently used biochemical methods and may complement . involving such measures as correct positioning and supporting of the infant and muscle strengthening. it usually takes about two months. and idiopathic osteoporosis. or all cases categorized as type I-IV.12-14 However.2 In one study. it may be possible to convert severe forms of OI into type I OI by using targeted gene therapy to insert a null mutation into the COL1A gene harboring the OI-associated mutation. originally considered one of the defining hallmarks of type I OI. a somatic mutation in a type I collagen gene occurred during embryonic development of the parent. In severe cases of OI (type II and III). such as Ehlers-Danlos Syndrome type VII. Diagnosis of OI can also be achieved through genetic testing for mutations in COL1A1 or COL1A2. In rare cases of type III OI. it is critical to diagnose OI as early as possible. Thus. mutations in COL1A1 have been shown to be autosomal recessive. Milder forms of OI (types I and IV-VII) may be more difficult to diagnose. the long-term effects of bisphosponate treatment. OI types V-VII appear to be due to mutations in other. mutations in COL1A1 and COL1A2 are also associated with other phenotypes.19 In these cases. Since biochemical testing requires expansion of fibroblast cultures in vitro. management of OI is largely preventive.10 bone quality over time. By contrast.18 Up to 20% of apparently sporadic mutations may be due to parental mosaicism.1 In the future. which may compromise Genetic Testing for OI The Osteogenesis Imperfecta Evaluation detects mutations in COL1A1 and COL1A2. OI-associated mutations in COL1A1 or COL1A2 lead either to a reduction in the amount of type I collagen produced or to a change in its electrophoretic mobility. as yet unidentified genes. Many of the characteristic signs of OI – such as hearing loss.Diagnosis of OI OI is suspected from fractures without or with minimal trauma.20 but the recurrence rate of OI in children of mosaic carriers may be as high as 50%. genetic testing for OI at birth is advised for siblings of children with OI. and DI – only become apparent over time. Of note. atypical Marfans Syndrome. and the cell harboring the mutation gave rise to germline as well as somatic cells. Mosaic individuals themselves typically show either a mild or no OI phenotype.16 Genetics of OI At least 90% of all cases of OI.
et al. Glorieux FH. www. Ward LM. 20. et al (1979) J Med Genet 16:101-16. et al (1984) J Biol Chem 259:12941-4. et al (2004) Lancet 363:1377-85. 15. 9. et al (2000) J Clin Endocrinol Metab 85:1846-50. et al (1997) Acta Paediatr 86:711-8. to 6:30 p. 19. potentially forcing a lengthy separation of infant and parents. 11. Athena Diagnostics and the Athena Diagnostics logo are registered trademarks of Athena Diagnostics. 13. Sequencing results are interpreted. Blumsohn A. 12. et al (2002) Arch Dis Child 86:356-64. Inc. 18. Eastern Time (US).com/endocrinetests/. 14. 10. et al (2002) Bone 31:12-8. The coding sequences of COL1A1 and COL1A2 are amplified in a highly specific manner through a polymerase chain reaction (PCR). Inc. Correlagen is a registered trademark of Correlagen. where non-traumatic fractures due to OI can be misinterpreted as signs of child abuse. Marlowe A. et al (1994) J Biol Chem 269:14751-8. et al (2004) Hum Mutat 23:399-400. Ries-Levavi L. (2002) J Bone Miner Res 17:30-8. Astrom E.m. 7. 2. Rauch F. 4. Customers in the US and Canada please call toll-free 800-394-4493 x2 Non-US customers please call 508-756-2886 or fax 508-753-5601. Cohen-Solal L. et al (2004) Am J Hum Genet 74:752-60. Testing performed under license from Correlagen. Inc. et al (2002) J Med Genet 39:382-6. 5. Suite 1100. et al (2001) Am J Med Genet 100:280-6.correlagen. et al (2004) Science 303:1198-201. Glorieux FH. Prompt diagnosis of OI is also important in infants with a family history of OI. so that preventive measures to minimize bone fractures can be taken without delay. • 222 Third Street. Cambridge.AthenaDiagnostics. and a detailed result report is sent to the patient’s physician.biochemical studies in establishing a firm diagnosis. Plotkin H. et al (1992) J Clin Invest 89:567-73. How Is Genetic Testing for OI Performed? DNA for sequencing is obtained from leukocytes present in a small blood sample. et al (2001) Hum Mutat 17:434. Shapiro JR. 17. and all PCR products are fully sequenced. Athena Diagnostics’ Customer Service Representatives are available from 8:30 a. Sillence DO. Zolezzi F.correlagen. This is especially important in infants. 6. 16.com References: 1. et al (2000) J Bone Miner Res 15:1650-8. 8. 3.m. Cabral WA. Chamberlain JR. et al (1997) Am J Med Genet 71:366-70. Marini JC (2003) N Engl J Med 349:423-6. ADX101SG-3/05AW-REV00 . Glorieux FH. MA 02142 • www. For the current number of OI-associated variants in COL1A1 or COL1A2. Ward LM. please visit: http://www. et al (1998) N Engl J Med 339:947-52. Lund AM. Pihlajaniemi T.com For information on ordering the Osteogenesis Imperfecta Evaluation.
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