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Bone Diseases Dr Derakhshandeh, PhD.

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1 Bone Diseases Dr Derakhshandeh, PhD

2 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 Marfan syndrome Fibrillin gene

5 Osteogenesis imperfecta

6 Osteogenesis imperfecta

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

8 Collagen Fibrillin 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
extracellular glycoprotein 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 I OSTEOGENESIS 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

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23 Glycine Serin

24 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

25 Arthrochalasia

26 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

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

28 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

29 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

30 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

31 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

32 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

33 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

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

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

36 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-normal stature

37 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

38 CLINICAL FEATURES OI

39 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

40 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

41 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

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

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

44 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%)

45 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

46 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

47 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

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

49 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

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

51 Symptoms not all people with OI will have blue sclerae or hearing loss
All do have fragile bones, but not all people with OI actually ever break a bone penetrance of hearing loss is clearly age-dependent (Garretsen and Cremers, 1991)

52 SKIN Skin elasticity OI type I increased elasticity in comparison to the type III patients

53 INHERITANCE Paternal age effect:
for increased risk of new mutations has been documented although it appears to be considerably lower than, for example, in Achondroplasia Blumsohn et al. (2001) confirmed the presence of a small paternal age effect in apparently sporadic OI

54 CLINICAL FEATURES OII

55 OSTEOGENESIS IMPERFECTA CONGENITA,
NEONATAL LETHAL FORM OSTEOGENESIS IMPERFECTA, TYPE II OI Gene map locus 17q21.31-q22, 7q22.1

56 OSTEOGENESIS IMPERFECTA, TYPE II

57 Osteogenesis imperfecta, type II:
the most severe form of the disorder Infants with the disorder: have soft, fragile bones that may appear bent or crumpled Bones are easily broken and multiple fractures can occur even before birth The chest is narrow with short ribs and underdeveloped lungs

58 Osteogenesis imperfecta, type II
Affected infants: have short bowed arms and legs; and unusually soft skull bones Characteristic facial features include a small, narrow nose and a dark blue tint to the part of the eyeball that is usually white Most infants with this condition are stillborn or die shortly after birth, usually from respiratory problems. A few children have lived from several months to a few years

59 CLINICAL FEATURES OIII

60 OSTEOGENESIS IMPERFECTA, TYPE IIIOI
Gene map locus 17q21.31-q22, 7q22.1 The causative mutation in most cases lies in one of the genes for type I collagen, COL1A1 or COL1A2

61 TYPE III OI

62 TYPE III OI People with the disorder are much shorter than average
because the condition prevents bones from growing normally. Spinal curvature (scoliosis) and bone abnormalities often become progressively worse during childhood but tend to stabilize during adolescence These complications may shorten a person's lifespan by affecting heart and lung function Other signs and symptoms include a light blue tint to the part of the eyeball that is usually white , brittle and discolored teeth, loose joints, and, in some cases, hearing loss.

63 Gene Therapy Chamberlain et al. (2004)
used adeno-associated virus vectors to disrupt mutant COL1A1 collagen genes in mesenchymal stem cells, from individuals with severe OI demonstrating successful gene targeting in adult human stem cells

64 CLINICAL FEATURES OI IV

65 OSTEOGENESIS IMPERFECTA, TYPE IV
OI, TYPE IV OSTEOGENESIS IMPERFECTA WITH NORMAL SCLERAE Gene map locus 17q21.31-q22

66 OSTEOGENESIS IMPERFECTA, TYPE IV

67 Hypothesis more than one broken bone occurring in a single episode (multiple) present at birth occuring after only minor trauma a minority of people with OI never break a bone deformed or short extremities (such as leg deformities or arm deformities) deafness (conductive hearing loss may occur in adults)

68 Hypothesis Short stature tooth abnormalities low nasal bridge
easy bruising bowed legs

69 Signs and tests A physical examination may confirm the presence of fractures, deformities, and other symptoms. Bone X-rays may show multiple healed fractures. Once the specific molecular diagnosis is known, family members can be tested by a DNA blood test. DNA testing on prenatal chorionic villus samples (CVS) can make the diagnosis during pregnancy. Severe OI is visible on prenatal ultrasound as early as 16 weeks.

70 Osteomyelitis

71 Osteomyelitis Procedure
Osteomyelitis is an acute or chronic bone infection, usually caused by bacteria or by fungus

72 Causes, incidence, and risk factors Osteomyelitis
The infection that causes osteomyelitis: often is in another part of the body and spreads to the bone via the blood Affected bone may have been predisposed to infection because of recent trauma In children: the long bones are usually affected In adults: the vertebrae and the pelvis (hip) are most commonly

73 Osteomyelitis Risk factors are recent trauma, diabetes, hemodialysis, and intravenous drug abuse. People who have had their spleen removed are also at higher risk for osteomyelitis The incidence of osteomyelitis is 2 in 10,000 people.

74 Prevention Prompt and complete treatment of infections is helpful
High-risk people should see a health care provider promptly if they have signs of an infection anywhere in the body

75 Symptoms Pain in the bone Local swelling redness and warmth Fever
General discomfort, uneasiness, or ill feeling

76 Achondroplasia

77 Achondroplasia Definition An inherited disorder of bone growth
that causes the most common type of dwarfism

78 Achondroplasia its characteristic normal to large-sized head
shortened arms and legs (especially the upper arm) a normal-sized trunk and waddling gait

79 Achondroplasia Achondroplasia is inherited as an (AD) trait
However, the majority of cases, approximately 80%, appear as spontaneous mutations If one parent has Achondroplasia, the infant has a 50% chance of inheriting the disorder If both parents have the condition, the infant's chances of being affected increase to 75%

80 Genetics of Achondroplasia
99% of the affected individuals: a single point mutation in the Fibroblast Growth Factor Receptor gene3 (FGFR 3) located on chromosome 4 glycine is substituted for arginine at codon 380 of FGFR 3

81 Such a mutation results:
in an abnormal cartilage and fibrous connecting tissue formation Therefore, not only bones, but the ligaments, tendons and muscles of the patient with Achondroplasia are affected

82 Family with compound heterozygosity for N540K and G380R mutations

83 Prevention Genetic counseling may be helpful for prospective parents:
when one or both have achondroplasia Because achondroplasia arises as a spontaneous mutation: absolute prevention is not possible

84 Symptoms Short stature short limbs large appearing head
at birth: Short stature short limbs large appearing head Skeletal (limb) abnormality Abnormal hand appearance with persistent space between the long and ring fingers marked kyphosis and lordosis (spine curvatures)

85 kyphosis and lordosis

86 Symptoms Waddling gait prominent forehead (frontal bossing)
increased inward curve of lower back increased outward curve of upper back making back appear slightly hunched (kyphosis) head appears disproportionately large for body bowed legs


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