What causes osteogenesis imperfecta (OI)?

Answer

Type 1 collagen is a triple helix formed by two copies of the alpha₁ chain and one copy of the alpha₂ chain. The COL1A gene on chromosome 17 encodes the pro-alpha₁ chain, and the COL2A gene on chromosome 2 encodes the pro-alpha₂ chain.^[13]

The gene sequence coding for the triple-helix domain has a repeating motif of (Gly-X-Y)(n), where X is commonly hydroxyproline and Y is commonly hydroxylysine. Glycine, being the smallest of all amino acids, fits into the core of the superhelix when the chains wind around each other; therefore, glycine plays an important role in the superhelix formation.

In 85-90% of cases, the gene mutation occurs in the region where the exon and intron splice sites are sequenced. All current mutations for type 1 collagen and their associated phenotypes can be found in the Human Type 1 Collagen Mutation Database.

In OI due to quantitative defects of type 1 collagen, mutations are usually found on the COL1A gene. The mutations result in the production of a premature stop codon or a microsense frame shift, which leads to mutant messenger RNA (mRNA) in the nucleus. However, the cytoplasm contains normal alpha₁ mRNA; therefore, reduced amounts of structurally normal collagen are produced.

In OI due to qualitative defects of type 1 collagen, autosomal dominant mutations are found on either the COL1A or the COL1B gene. The mutations result in the production of a mixture of normal and mutant collagen chains. Substitution of a larger amino acid (eg, cysteine or alanine) for glycine results in abnormal helix formation, but these chains can combine with normal chains to produce type 1 collagen. The type 1 collagen thus formed is functionally impaired because of the mutant chain; this is the so-called dominant negative mechanism.

Wallace et al, in a report on three patients who had type I OI and primary open angle glaucoma (POAG), identified two novel mutations in COL1A1 in these individuals.^[14]They suggested that some mutations in COL1A1 may be causative for OI and POAG. Alternatively, susceptibility genes may interact with mutations in COL1A1 to cause POAG.

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Media Gallery

Osteogenesis imperfecta. Acute fractures are observed in radius and ulna. Multiple fractures can be seen in ribs. Old healing humeral fracture with callus formation is observed.
Osteogenesis imperfecta. Beaded ribs. Multiple fractures are seen in long bones of upper extremities.
Osteogenesis imperfecta. Wormian bones are present in skull.
Osteogenesis imperfecta. Newborn has bilateral femoral fractures.

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Author

Manoj Ramachandran, MBBS, MRCS, FRCS Consultant Trauma and Orthopaedic Surgeon, Barts and the London NHS Trust; Honorary Senior Lecturer, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary's, University of London, UK

Manoj Ramachandran, MBBS, MRCS, FRCS is a member of the following medical societies: British Orthopaedic Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Orthopediatrics, Inc<br/>Serve(d) as a speaker or a member of a speakers bureau for: Orthopediatrics, Inc<br/>Received income in an amount equal to or greater than $250 from: Orthopediatrics, Inc.

Coauthor(s)

Pramond Achan, MBBS, FRCS Senior Registrar, Royal National Orthopaedic Hospital, UK

Disclosure: Nothing to disclose.

David H A Jones, MBChB, FRCS, FRCS(Ed)(Orth) Consultant Orthopedic Surgeon, Great Ormond Street Hospital for Children; Senior Clinical Lecturer, University College London Hospitals, UK

David H A Jones, MBChB, FRCS, FRCS(Ed)(Orth) is a member of the following medical societies: British Orthopaedic Association

Disclosure: Nothing to disclose.

Vinod K Panchbhavi, MD, FACS Professor of Orthopedic Surgery, Chief, Division of Foot and Ankle Surgery, Director, Foot and Ankle Fellowship Program, Department of Orthopedics, University of Texas Medical Branch School of Medicine

Vinod K Panchbhavi, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American College of Surgeons, American Orthopaedic Association, American Orthopaedic Foot and Ankle Society, Orthopaedic Trauma Association, Texas Orthopaedic Association

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Styker.

Chief Editor

Harris Gellman, MD Consulting Surgeon, Broward Hand Center; Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami, Leonard M Miller School of Medicine; Clinical Professor of Surgery, Nova Southeastern School of Medicine

Harris Gellman, MD is a member of the following medical societies: American Academy of Medical Acupuncture, American Academy of Orthopaedic Surgeons, American Orthopaedic Association, American Society for Surgery of the Hand, Arkansas Medical Society, Florida Medical Association, Florida Orthopaedic Society

Disclosure: Nothing to disclose.

Acknowledgements

Peter R Calder, MBBS, FRCS(Eng), FRCS (Tr&Orth) Consulting Surgeon, Department of Pediatric Orthopedic Surgery, The Royal National Orthopaedic Hospital, UK

Peter R Calder, MBBS, FRCS(Eng), FRCS (Tr&Orth) is a member of the following medical societies: British Medical Association

Disclosure: Nothing to disclose.

Ian D Dickey, MD, FRCSC Adjunct Professor, Department of Chemical and Biological Engineering, University of Maine; Consulting Staff, Adult Reconstruction, Orthopedic Oncology, Department of Orthopedics, Eastern Maine Medical Center

Ian D Dickey, MD, FRCSC is a member of the following medical societies: American Academy of Orthopaedic Surgeons, British Columbia Medical Association, Canadian Medical Association, and Royal College of Physicians and Surgeons of Canada

Disclosure: Stryker Orthopaedics Consulting fee Consulting; Cadence Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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