Osteogenesis Imperfecta

From Science Online

1 Introduction
2 Symptons
3 Collagen
4 Biochemistry
5 Treatment
6 References

Introduction

Osteogenesis Imperfecta is a group of genetic diorders. Osteogenesis Imperfecta means imperfect bone formation. The majority of people who have Osteogenesis Imperfecta do not have the correct amount of collagen or cannot produce collagen. Collagen is the most abundant protein in humans. Collagen is a component in bones, teeth, ligaments, and tendons. Collagen, in a crystalline form, fills out the cornea. There are eight different types of OI, ranging from mild (Type I) to severe (Type II)

Osteogensis Imperfect affects an estimated 6 to 7 per 100,000 people worldwide. 35% of children who have OI have no previous family history of OI, this is usually because of a new mutation to a gene.

Some Alernate Names for Osteogensis Imperfecta are :Brittle bone disease, Fragilitas ossium , OI, and Vrolik disease

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Symptons

The Symptons of Osteogensis Imperfecta depends on what type the person has.

Type I

Mildest and most common form of OI. 50 percent of people with OI have Type I. People with Type I have few fractures and limb deformities. Blue sclerae may be present.

Blue Sclerae

Hearing loss may occues in childhood or young adulthood. Type I is normally dominatly inheirated from a parent, or a mutation. Some biochemical test on cultured skin fibroblasts showed that there was a lower amount of type I collagen, but the collagen structure is normal. A few signs of Type I OI are multiple fractures of long bones, compression fractures of the vertebrae, and chronic pain.

Type II

Type II is the most severe form of OI. Infants with AType II have short limbs, small chests, and soft skulls, the legs of the infants are often in a frog-leg position. They have low birth weights, very dark blue or gray sclerae,intrauterine fractures and underdeveloped lungs. Some characteristic radiologic features are absent or limited calvarial mineralization; flat vertebral bodies; broad femurs; beaded and often broad short ribs; and evidence of malformation of the long bones. Many infants with Type II OI die within weeks of delivery. OI Type II results from a new dominant mutation in a type 1 collagen gene or parental mosaicism.

Type III

Type III Oi, is severe among children, who survive the neonatal period. Infants generally have mildly shortened and bowed limbs, small chests, and a soft calvarium. Also it is common for infants to have a triangular facial shape. A white, tinted blue, purple, or gray sclera. Type III is characterized by dominant mutations in type I collagen genes.The mutations are often spontaneous. Extremely severe types of OI, Type III, are caused by recessive mutations to other genes. Type III is characterized by structurally defective type I collagen. This type of collagen reduced amounts in the bone matrix.

Type IV

Type IV can be diagnosed at birth but normally symptons will not occur until later. People have a bowing of the long bones

Bowing of Long Bones

,a moderate-to-severe growth retardation, a short humerus and femur,the sclerae is often light blue in infancy, but the intensity varies. The sclerae may lighten to white later in childhood or early adulthood.

OI Type IV has an autosomal dominant pattern of inheritance, new mutations are the result of new cases. A structurally defective type I collagen is present in reduced amounts in the bone.

Type V

OI Type V is similar to OI Type IV . The most noticeble difference are large, hypertrophic calluses in the largest bones at fracture or surgical procedure sites. Calcification of the interosseous membrane between the radius and ulna restricts forearm rotation and may cause dislocation of the radial head. OI Type V is dominantly inherited.

Type VI

OI Type VI is extremely rare.Type VI is moderate in severity and similar in appearance OI Type IV. Type VI is distingushible by a mineralization defectin biopsied bone. The mode of inheritance has not yet been identified.

Type VII

Type VII somewhat resembles OI Type IV. Other cases can resemble OI Type II except that the children have white sclerae, small heads and round faces. Short stature and coxa vara is common OI Type VII results from recessive inheritance of a mutation in the CRTAP gene.

Type VIII

Similar to OI Types II or III in symptoms except for white sclerae. Type VIII is characterized by severe growth deficiency and extreme under-mineralization of the skeleton. Type III OI is caused by an absence or severe deficiency of prolyl 3-hydroxylase activity due to a mutation in the LEPRE1 gene.

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Collagen

Collagen is made up of three polypeptide strands, the three strands are left-handed helixs. The helices are twisted together into a right-handed coiled coil, which is known as a triple helix. This structure is held together by many hydrogen bonds.

1K6F Collagen

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Biochemistry

Mutations in the COL1A1, COL1A2, CRTAP, and LEPRE1 genes cause osteogenesis imperfecta.Around 90% of the cases inolve the COL1A1 and COL1A2 genes. Mutatation in the CRTAP and LEPRE1 genes are responsible for the rare and most severe cases of osteogenesis imperfecta.

COL1A1 COL1A2 Collagen type I is the major structural protein of bones, skins, and tendons. Collagen It consists of two alpha and one beta chain. These chains are synthesized in endoplasmic reticulum in a procollagen form with N- and C-terminal extensions. The central region of collagen contains of 338 repeating Gly-Xaa-Yaa triplets,the proline residue is also frequently incorporated into the Xaa and Yaa position.

The major cause of osteogensis imperfecta is a mutation that results in the replacing of one Gly with another protein in the repeating triplet pattern. Some of the other casues are the deletions or insertions of small fragments of the sequence. Some studies have been performed and scientists have discovered that most of the mutation sites range over the 1,014-residue triple helix of both the aplha 1 (I) and alpha 2 (I) chains. The most common replacements for Gly have Ser and Cys.

There has been many discussions on whether some of the protein substitutions can lead to lethal cases, and others result in milder forms. Although these seems to be the case no simple correlation has been observed relating clinical severity with the chain type, mutation site, flanking sequences, or residue substituted for Gly. They beleive that this many be the case because some studies showed that Gly 220 Ala mutation in the alpha 1 chain leads to moderate OI type IV, whereas Gly220Asp is lethal. (Konrad, 2000)

CRTAP

The Cartilage-Associated Protein

CRTAP contains 2 potential N-glycosylation signals.

In genomic DNA from an affected member with osteogenesis imperfecta type VII, they fou a single-nucleotide change (-1021C-G) in intron 1 of the CRTAP gene consistent with activation of a cryptic splice donor site and the inclusion of a 73-bp cryptic exon (position -1094 to -1021 5-prime of exon 2) into the CRTAP cDNA. Simialr deletions and insterations of this gene were found in OI Type IIB cases. (Online Mendelian Inheritance in Man)

LEPRE1 Leucine- and Proline- Enriched Proteoglycan 1

The LEPRE1 gene contains 15 exons.

Loss of function mutations in the LEPRE1 gene cause abnormal collagen helix formation and abnormal bone development leading to OI. In cases involving OI Type VIII, they found homozygosity for a splice site mutation of the LEPRE1 gene, mutation in the LEPRE1 gene, and a transversion in the LEPRE1 gene that resulted in a tyr552-to-ter substitution (Y552X). (Online Mendelian Inheritance in Man)

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Treatment

As of yet there is no treatment for Osteogensis Imperfecta. There are therapies can reduce pain and complications. One option to help reduce the pain is bisphosphonates, bisphosphonates can increase the strength and density of bone in peopleI. They also have been shown to reduce bone pain and fracture rate For more severe cases, surgery will place metal rods into the long bones of the legs, to help strengthenthe bone and reduce the risk of fracture. Bracing can also be helpful for some people. Reconstructive surgery may also be necessary to correct any deformities.

Low impact exercises such as swimming can help keep muscles strong and maintain strong bones. This type of excerise is encouraged for people with OI.

http://www.umm.edu/ency/article/001573trt.htm

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