Osteogenesis imperfecta (OI) is caused by mutations in the genes that code for type I procollagen (ie, COL1A1 and COL1A2).
The most common classification for OI was developed by Sillence. The following types of Osteogenesis imperfecta have been reported:
- Type I – Mild forms
- Type II – Extremely severe
- Type III – Severe
- Type IV – Undefined
A few patients with many of the symptoms of OI were recently found not to have mutations in the genes for type I collagen. These patients have a characteristic lamellar patterning of bone, and distinctive clinical and radiological findings. They have been assigned the classifications of types V, VI, and VII OI.
- Type V- Moderate to Severe
- Type VI- Moderate to severe
- Type VII- Moderate
Type V and VI differ in terms of inheritance.
The classification OI is not always prognostic because of variations in the clinical course. Some patients appear normal at birth and become progressively worse; others have multiple fractures in infancy and childhood, improve after puberty, and fracture more frequently later in life. Women are particularly prone to fracture during pregnancy and after menopause. A few women from families with mild variants of OI do not develop fractures until after menopause, and their disease may be difficult to distinguish from postmenopausal osteoporosis.
- Autosomal dominant for Type I,III,IV and V
- Autosomal recessive for Type VII, rarely AR for type II and III
- Sporadic for type II
- Inheritance of Type VI is unknown
Type I OI has a frequency of about 1 in 30,000. Type II OI has a reported incidence at birth of about 1 in 60,000, but the combined incidence of the three severe forms that are recognizable at birth (types II, III, and IV) may be much higher. Only a few patients with types V, VI, and VII have been reported.
Type I collagen fibers are found in the bones, organ capsules, fascia, cornea, sclera, tendons, meninges, and dermis. Type I collagen, which constitutes approximately 30% of the human body by weight, is the defective protein in Osteogenesis imperfecta. Qualitative defects (eg, an abnormal collagen I molecule) and quantitative defects (eg, decreased production of normal collagen I molecules) are described.
i) Skeletal effects
- In type I OI, the fragility of bones may be severe enough to limit physical activity or be so mild that individuals are unaware of any disability. Radiographs of the skull in patients with mild disease may show a mottled appearance because of small islands of irregular ossification.
- In type II OI, bones and other connective tissues are so fragile that massive injuries can occur in utero or during delivery. Ossification of many bones is frequently incomplete. Continuously beaded or broken ribs (figure-1) and crumpled or bent long bones (accordina femora) may be present (figure-2). The long bones may be either thick or thin.
Figure-1- Beaded ribs in OI
Figure-2- Bent long bones in OI
- In types III and IV, multiple fractures from minor physical stress can produce severe deformities.The appearance of “popcorn-like” deposits of mineral in x-rays of the ends of long bones is an ominous sign.
In all forms of OI, bone mineral density is decreased. Surprisingly, fractures appear to heal normally.
ii) Ocular Features
The sclerae can be normal, slightly bluish, or bright blue (figure-3). The color is probably caused by a thinness of the collagen layers of the sclerae that allows the choroid layers to be seen. Blue sclerae, however, are an inherited trait in some families who do not have increased bone fragility. Blue sclera is not found in type IV, V, VI and VII.
Figure-3- Blue sclera in OI
The teeth may be normal, moderately discolored, or grossly abnormal. The enamel generally appears normal, but the teeth may have a characteristic amber, yellowish brown, or translucent bluish gray color because of improper deposition or deficiency of dentin (figure-4).The deciduous teeth are usually smaller than normal, whereas permanent teeth are frequently bell-shaped and restricted at the base. In some patients, the teeth readily fracture and need to be extracted. The defect in dentin is directly attributable to the fact that normal dentin is rich in type I collagen.
Figure-4- Dental defects in OI
IV) Hearing Loss
Hearing loss usually begins during the second decade of life and occurs in more than 50% of individuals over age 30. The middle ear usually exhibits maldevelopment, deficient ossification, persistence of cartilage in areas that are normally ossified, and abnormal calcium deposits.
V) Other Features
Changes in other connective tissues can include thin skin that scars extensively, joint laxity with permanent dislocations and, occasionally, cardiovascular manifestations such as aortic regurgitation, mitral incompetence, and fragility of large blood vessels. For unknown reasons, some patients develop a hyper metabolic state with elevated serum thyroxin levels, hyperthermia, and excessive sweating .
- OI is usually diagnosed on the basis of clinical criteria.
- The presence of fractures together with blue sclerae, dentinogenesis imperfecta, or family history of the disease is usually sufficient to make the diagnosis.
- Other causes of pathologic fractures must be excluded, including battered child syndrome, nutritional deficiencies, malignancies, and other inherited disorders such as hypophosphatasia.
- The absence of superficial bruises can be helpful in distinguishing OI from battered child syndrome.
- X-rays usually reveal a decrease in bone density that can be verified by photon or x-ray absorptiometry.
- Bone microscopy can be helpful in the diagnosis.
- A molecular defect in type I procollagen can be demonstrated in over two-thirds of patients by incubating skin fibroblasts with radioactive amino acids and then analyzing the proα chains by polyacrylamide gel electrophoresis.
- After a mutation in a type I procollagen gene is identified, a simple PCR test can be used to screen family members at risk or for prenatal diagnosis.
- Those with mild disorder may need little treatment when fractures decrease after puberty,
- Women require special attention during pregnancy and after menopause, when fractures again increase.
- More severely affected children require a comprehensive program of physical therapy, surgical management of fractures and skeletal deformities, and vocational education
- Moderately to severely affected patients should be evaluated periodically to anticipate possible neurologic problems.
- Counseling and emotional support are important for patients and their parents.
In normal healthy tissues where the collagen is fully hydroxylated and in a triple helical structure, the molecule is resistant to attack by most proteases. Under these normal healthy conditions, only specialized enzymes called collagenases can attack the collagen molecule.
The group of collagenases belong to a family of enzymes called matrix metalloproteinases or MMPs.
Many cells in our body can synthesize and release collagenase including fibroblasts, macrophages, neutrophils, osteoclasts, and tumor cells. One of the reasons that some cancer cells can be so invasive is because they release potent collagenases that can break down the collagen around them.They can also break down the basement membranes of blood vessels and spread throughout the body. In chronic pressure ulcers, there is a massive invasion of neutrophils, and they release a very potent collagenase called MMP-8 that is responsible for connective tissue breakdown.
Physiological turn over
During growth and development, the collagen fibrils in all tissues undergo repeated synthesis, degradation, and resynthesis. In adults, collagen fibers in most tissues undergo very little metabolic turnover. One exception is bone where collagen fibrils are degraded and resynthesized as part of lifelong remodeling.
Increased collagen degradation occurs with advancing age and also in sun exposed areas. Loss of elasticity and strength results in sagging skin and wrinkles. However, collagen maintains its structural integrity for longer if it is protected from environmental threats like UV exposure.
Variations in collagen turn over
A) The rate of collagen degradation increases under some circumstances
I) In starvation, a large fraction of the collagen in skin and other connective tissues is degraded, thus providing amino acids for gluconeogenesis .
2) Large losses of collagen also occur in most connective tissues during immobilization or prolonged periods of low-gravitational stress.
3) In rheumatoid arthritis, a rapid degradation of collagen occurs in the articular cartilage.
4) In cancer and chronic nonhealing ulcers, the extent of collagen degradation can be quite extensive
B) Deceased collagen synthesis
Glucocorticoids decrease the collagen content of most connective tissues, including bone, by decreasing the rate of collagen synthesis. Decreases in collagen weaken tissues.
C) Excess collagen deposition
In many pathologic states, however, collagen is deposited in excess.
1) Post inflammation- With injury to tissue, inflammation is usually followed by increased deposition of collagen fibrils in the form of fibrotic tissue and scars.
2) Post repair- The deposition of collagen fibrils during the repair process is largely irreversible and is a major feature of the pathological changes in hepatic cirrhosis, pulmonary fibrosis, atherosclerosis, and nephrosclerosis.
Disorders associated with collagen synthesis
A number of genetic diseases result from abnormalities in the synthesis of collagen. Some diseases are due to mutations in collagen genes or in genes encoding some of the enzymes involved in these posttranslational modifications (Table).
Table – Diseases caused by mutations in collagen genes or by deficiencies in the activities of enzymes involved in the posttranslational modification of collagen
|Gene or Enzyme||Disease|
|COL1A1, COL1A2||Osteogenesis imperfecta, type 1|
|Ehlers-Danlos syndrome type VII autosomal dominant|
|COL3A1||Ehlers-Danlos syndrome type IV|
|COL7A1||Epidermolysis bullosa, dystrophic|
|COL10A1||Schmid metaphysial chondrodysplasia|
|Lysyl hydroxylase||Ehlers-Danlos syndrome type VI|
|Procollagen N-proteinase||Ehlers-Danlos syndrome type VII autosomal recessive|
|Lysyl hydroxylase(Secondary to deficiency of copper)||Menke’s disease|
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e) β Myosin heavy chain
The right answer is – c) Collagen.
Osteogenesis imperfecta (OI) is predominantly characterized by a generalized decrease in bone mass (osteopenia) and by brittle bones. The disorder is frequently associated with blue sclerae, dental abnormalities (dentinogenesis imperfecta), progressive hearing loss, and a positive family history.
The disorder is caused by mutations in the genes that code for type I procollagen (ie, COL1A1 and COL1A2).
General discussion of collagen
Collagen is the most abundant protein of the human body accounting to around 25-30% of the total protein content. It is the major component of most connective tissues. It is also the main fibrous component of skin, bone, tendon, cartilage, and teeth. Collagen is a Greek word which means “Glue”, it is so named since it holds the cells together in the tissues.
Types of collagen
Twenty-eight different collagens made up of over 30 distinct polypeptide chains (each encoded by a separate gene) have been identified in human tissues. Many are minor constituents that probably have highly specialized functions. They may play important roles in determining the physical properties of specific tissues.
In addition, a number of proteins (eg, the C1q component of the complement system, pulmonary surfactant proteins SP-A and SP-D) that are not classified as collagens have collagen-like domains in their structures; these proteins are sometimes referred to as “noncollagen collagens.”
The major types are as follows-
1) Type I collagen is found throughout the body except in cartilaginous tissues. It is found in skin, tendon, vascular, ligature, organs and is the main component of bone. It is also synthesized in response to injury and in the fibrous nodules in fibrous diseases. Over 90% of the collagen in the body is type I.It is synthesized from the genes COL1A1, COL1A2. The mutations of these genes are responsible for ‘Osteogenesis Imperfecta“.
2) Type II collagen is the main component of cartilage. It is also found in developing cornea and vitreous humor. These are formed from two or more collagens or co-polymers rather than a single type of collagen.It is synthesized from the genes COL2A1.
3) Type III collagen is found in the extensible connective tissues such as skin, lung, and the vascular system such as walls of arteries and other hollow organs and usually occurs in the same fibril with type I collagen. The gene responsible for this is COL3A1.
4) Type IV collagen forms the bases of cell basement membrane. The genes for this type are COL4A1–COL4A6
5) Type V collagen is a minor components of tissue and occurs as fibrils with type I and type II collagen respectively. Type V forms cell surfaces, hair and placenta. It is synthesized from COL5A1–COL5A3.
6) Type VI Collagen is present in most connective tissues and is derived from the genes COL6A1–COL6A3.
Structure of collagen
All collagen types have a triple helical structure. In some collagens, the entire molecule is triple helical, whereas in others the triple helix may involve only a fraction of the structure.
Mature collagen type I, containing approximately 1000 amino acids, belongs to the former type; in it, each polypeptide subunit or alpha chain is twisted into a left-handed helix of three residues per turn. Three of these alpha chains are then wound into a right-handed superhelix, forming a rod-like molecule 1.4 nm in diameter and about 300 nm long (Figure-1).
Figure-1- Each individual polypeptide chain is twisted into a left-handed helix of three residues (Gly-X-Y) per turn, and all of these chains are then wound into a right-handed superhelix.
Amino acid composition of collagen
A striking characteristic of collagen is the occurrence of glycine residues at every third position of the triple helical portion of the alpha chain. This is necessary because glycine is the only amino acid small enough to be accommodated in the limited space available down the central core of the triple helix. This repeating structure, represented as (Gly-X-Y)n, is an absolute requirement for the formation of the triple helix. While X and Y can be any other amino acids, about 100 of the X positions are proline and about 100 of the Y positions are hydroxy proline. Proline and hydroxy proline confer rigidity on the collagen molecule.
Hydroxylation of Proline and Lysine
Hydroxy proline is formed by the posttranslational hydroxylation of peptide-bound proline residues catalyzed by the enzyme prolyl hydroxylase, whose cofactors are ascorbic acid (vitamin C) and α-ketoglutarate. Vitamin C deficiency causes impaired hydroxylation , and defective collagen synthesis and hence is responsible for the disease scurvy. The hydroxylation is site specific, hence proline is hydroxylated to 4-hydroxy proline or 3-hydroxy proline depending upon its location relative to glycine.
Lysines in the Y position may also be posttranslationally modified to hydroxylysine through the action of lysyl hydroxylase, an enzyme with similar cofactors. Lysine is hydroxylated at position -5. The hydroxylated amino acids are of special functional significance.
Glycosylation of amino acyl residues in collagen
Some of these hydroxylysines may be further modified by the addition of galactose or galactosyl-glucose through an O-glycosidic linkage, a glycosylation site that is unique to collagen. The galactose and glucose residues are added sequentially by galactosyl and glucosyl transferases. The extent of glycosylation is different in different tissues (Figure-2).
Figure-2- Glycosylation of lysine residue in collagen.
Synthesis of collagen- To be continued in next post
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e) β Myosin heavy chain
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