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Bone Diseases

Bone Diseases. Dr Derakhshandeh, PhD. Dominant negative mutations. Dominant negative mutations: antimorphic mutations an altered gene product that acts antagonistically to the wild-type allele These mutations usually result in an altered molecular function (often inactive): Dominant

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Bone Diseases

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  1. Bone Diseases Dr Derakhshandeh, PhD

  2. Dominant negative mutations • Dominant negative mutations: • antimorphic mutations • an altered gene product that acts antagonistically to the wild-type allele • These mutations usually result in an altered molecular function (often inactive): • Dominant • or semi-dominant phenotype

  3. Dominant negative mutations • In humans: • Marfan syndrome is an example of a dominant negative mutation • occurring in an autosomal dominant disease • the defective glycoprotein product of the fibrillin gene (FBN1): • antagonizes the product of the normal allele

  4. Fibrillin gene Marfan syndrome

  5. Osteogenesis imperfecta

  6. Osteogenesis imperfecta

  7. Definition Osteogenesis imperfecta: a congenital (present from birth) condition of abnormal fragility of the bones

  8. CollagenFibrillin in EM

  9. Collagen • in most tissues and organs • is most plentiful in: • dermis • Tendon • Cartilage • and bone • as a scaffolding for our bodies • Controls cell shape • broken bones regenerate • and wounds heal

  10. Collagens • the fibrous protein constituent: • Insoluble • extracellularglycoprotein • found in all animals • the most abundant proteins in the human body

  11. Primary Structure of Collagens • The basic unit of collagens: • a polypeptide consisting of the repeating sequence • (Glycine (Gly) - X - Y)n • X is often Proline (Pro) • and Y is often hydroxyproline

  12. Procollagen Type I • The most common form of fibrillar collagen • It is a major constituent of: • bone • and skin • consists of a heterotrimer of: • two alpha1(I) • and one alpha2(I) chains

  13. Tertiary Structure

  14. Extracellular processes of collagen synthesis Prockop & Kivirikko (1984)

  15. Genetic • OI, TYPE IOSTEOGENESIS IMPERFECTA WITH BLUE SCLERA • Gene map locus 17q21.31-q22, 7q22.1 • OI type I phenotype can be produced by mutation in either the COL1A1 gene or the COL1A2 gene

  16. Osteogenesis imperfecta type I • 1:10 000 • dominantly inherited (AD) • Connective tissue disorder • characterized mainly by bone • fragility • blue sclera • 'functional null' alleles of COL1A1 on chromosome 17 • or COL1A2 on chromosome 7 • lead to reduced amounts of normal collagen I

  17. What is the official name of the COL1A1 gene? • The official name of this gene is: • “collagen, type I, alpha 1” • COL1A1 is the gene's official symbol

  18. Glycine Serin

  19. What conditions are related to the COL1A1 gene? Ehles-Donlos syndrome (AD) Arthrochalasia: (Short stature, Hyper elasticity of skin, AR, Problem with healing, N-Terminal defect caused by mutations in the COL1A1/2 gene

  20. Arthrochalasia

  21. The mutations in the COL1A1/2 gene • instruct the cell to leave out a part of the pro-alpha1(I) chain that contains a segment used to attach one molecule to another • When this part of the protein is missing, the structure of type I collagen is compromised • Tissues that are rich in type I collagen: • such as the skin, bones, and tendons, are affected by this change

  22. OI Type I • Osteogenesis imperfecta is the most common disorder • Mutations: inactivate one of the two copies of the COL1A1/2 gene:

  23. OI Type I • The mutated copy of the gene does not produce any pro-alpha1/2(I) collagen chains • Because only one copy of the gene: • cells from people with this disorder make only half of the normal amount of type I collagen: • which results in bone fragility and other symptoms

  24. OI Type II - caused by mutations in the COL1A1/2 gene • Many different types of mutations in the COL1A1/2 gene: can cause osteogenesis imperfecta type II • These mutations range: • from missing pieces of the COL2A1/2 gene • to amino acid substitutions • in which the amino acid glycine is replaced by another amino acid in the protein strand • C-terminal

  25. OI Type II • Sometimes one end of the gene (called the C-terminus) is altered • which interferes with the association of the protein strands • All of these changes prevent the normal production of mature type I collagen • which results in this severe condition, type II osteogenesis imperfecta

  26. OI Type III • caused by mutations in the COL1A1/2 gene • Mutations in the COL1A1/2 gene may result: • unusable for collagen production • Other mutations cause the amino acid glycine to be replaced by a different amino acid in the pro-alpha1(I) chain • inhibits the essential interaction between protein chains

  27. type III osteogenesis imperfecta • inability of the altered procollagen strands • These alterations negatively affect tissues that are rich in type I collagen • such as the skin, bones, teeth (Dentinogenesis imperfecta), and tendons

  28. OI Type (IV) • caused by mutations in the COL1A1/2 gene • Several different types of mutations in the COL1A1/2 gene cause osteogenesis imperfecta type IV • missing pieces of the COL1A1/2 gene • or changes in base pairs • formation of the mature triple-stranded collagen molecule

  29. OI • Position effect (5’/3’- Mutation) • Protein effect (Gly) • Chain effect (aI/aII)

  30. Where is the COL1A1 gene located? Cytogenetic Location: 17q21.3-q22.1 • Molecular Location on chromosome 17

  31. CLINICAL FEATURES Osteogenesis imperfecta: • Characterized chiefly by multiple bone fractures, usually resulting from minimal trauma • Affected individuals have blue sclerae, normal-near normal teeth, and normal or near-normalstature

  32. CLINICAL FEATURES Osteogenesis imperfecta: • Fractures are rare in the neonatal period; • fracture tendency is constant from childhood to puberty • Often increases following menopause in women and after the sixth decade in men

  33. CLINICAL FEATURES OI

  34. CLINICAL FEATURES • Fractures: • heal rapidly with evidence of a callus formation • and, with good orthopedic care, without deformity • Hearing loss; • occurs in about 50% of families • beginning in the late teens • to profound deafness, by the end of the fourth to fifth decade

  35. CLINICAL FEATURES • Radiologically: • wormian bones are common • but bone morphology is generally normal at birth • Vertebral body morphology: • in the adult is normal initially • but often develops the classic 'cod-fish' appearance

  36. EYES • Individuals with OI type I have distinctly blue sclera which remain intensely blue throughout life • The intensity of the blue fades with time: that these individuals may have sclerae of normal hue by adult life

  37. EYES • Hartikka et al. (2004) found that: • patients with COL1A1 mutations more frequently had blue sclerae than those with COL1A2 mutations

  38. CARDIOVASCULAR • Mitral valve prolapse occurred in 18% (3 times the prevalence in unaffected relatives)

  39. EARS • In likely heterogeneous groups of patients with OI: • about half of affected individuals have hearing loss • that begins during the second decade as a conductive loss • Audiometry showed hearing loss in 25 patients (59.5%)

  40. EARS • Hartikka et al. (2004) reported: • No correlation was found between the mutated gene or mutation type and hearing pattern • The authors interpreted this to mean that the basis of hearing loss in OI is complex • and that it is a result of multifactorial

  41. Causes, incidence, and risk factors • All four types of OI are caused by defects in the amount or • structure of Type 1 collagen • an important part of the bone matrix

  42. Causes, incidence, and risk factors • The defect may be inherited in an autosomal dominant pattern from an affected parent • This means that an affected parent, who carries a single gene for the disorder • has a 50% chance of having children with the disorder • Any child who inherits this gene will be affected

  43. Prevention • Genetic counseling: • is recommended for prospective parents if one or both are affected by this disorder

  44. Symptoms OI: • all of the bones are abnormally weak • The severity of the abnormality varies enormously from Type II OI • which is usually lethal in infancy (or even before birth) • Type I OI, which may be so mild that the diagnosis is not made, even in adulthood

  45. Symptoms • The three classic symptoms of OI includes: • fragile bones • early hearing loss • and whites of the eyes that appear bluish (blue sclerae)

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