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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 or semi-dominant phenotype 2 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 3 Marfan syndrome Fibrillin gene 4 Osteogenesis imperfecta 5 Osteogenesis imperfect 6 Definition Osteogenesis imperfecta: a congenital (present from birth) condition of abnormal fragility of the bones 7 Collagen Fibrillin in EM 8 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 9 Collagens the fibrous protein constituent: Insoluble extracellular glycoprotein found in all animals the most abundant proteins in the human body 10 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 11 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 12 Tertiary Structure 13 Extracellular processes of collagen synthesis Prockop & Kivirikko (1984) 14 OI, Genetic 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 15 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 16 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 17 18 19 20 21 22 Glycine Serin 23 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 24 Arthrochalasia 25 –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 26 OI Type I Osteogenesis imperfecta is the most common disorder Mutations: inactivate one of the two copies of the COL1A1/2 gene: 27 OI Type I •The mutated copy of the gene does not produce any proalpha1/2(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 28 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 29 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 30 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 31 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 32 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 33 OI Position effect (5’/3’- Mutation) Protein effect (Gly) Chain effect (aI/aII) 34 Where is the COL1A1 gene located? Cytogenetic Location: 17q21.3-q22.1 Molecular Location on chromosome 17 35 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 nearnormal stature 36 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 37 CLINICAL FEATURES OI 38 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 39 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 40 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 41 EYES Hartikka et al. (2004) found that: patients with COL1A1 mutations more frequently had blue sclerae than those with COL1A2 mutations 42 CARDIOVASCULAR Mitral valve prolapse occurred in 18% (3 times the prevalence in unaffected relatives) 43 In EARS 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%) 44 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 45 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 46 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 47 Prevention Genetic counseling: is recommended for prospective parents if one or both are affected by this disorder 48 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 49 Symptoms • • • • The three classic symptoms of OI includes: fragile bones early hearing loss and whites of the eyes that appear bluish (blue sclerae) 50 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) • 51 SKIN Skin elasticity OI type I increased elasticity in comparison to the type III patients 52 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 53 CLINICAL FEATURES OII 54 OSTEOGENESIS IMPERFECTA CONGENITA, NEONATAL LETHAL FORM OSTEOGENESIS IMPERFECTA, TYPE II OI Gene map locus 17q21.31-q22, 7q22.1 55 OSTEOGENESIS IMPERFECTA, TYPE II 56 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 57 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 58 CLINICAL FEATURES OIII 59 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 60 TYPE III OI 61 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. 62 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 63 CLINICAL FEATURES OI IV 64 OSTEOGENESIS IMPERFECTA, TYPE IV OI, TYPE IV OSTEOGENESIS IMPERFECTA WITH NORMAL SCLERAE Gene map locus 17q21.31-q22 65 OSTEOGENESIS IMPERFECTA, TYPE IV 66 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) 67 Hypothesis Short stature tooth abnormalities low nasal bridge easy bruising bowed legs 68 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 69 Osteomyelitis 70 Osteomyelitis Procedure Osteomyelitis is an acute or chronic bone infection, usually caused by bacteria or by fungus 71 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 72 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. 73 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 74 Symptoms Pain in the bone Local swelling redness and warmth Fever General discomfort, uneasiness, or ill feeling 75 Achondroplasia 76 Achondroplasia Definition An inherited disorder of bone growth that causes the most common type of dwarfism 77 Achondroplasia its characteristic normal to largesized head shortened arms and legs (especially the upper arm) a normal-sized trunk and waddling gait 78 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% 79 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 80 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 81 Family with compound heterozygosity for N540K and G380R mutations 82 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 83 Symptoms 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) 84 kyphosis and lordosis 85 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 86