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Osteogenesis Imperfecta

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Elle Ruggiero

on 19 March 2015

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Transcript of Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI)
Elle Ruggiero
COL1A1: Normal DNA Replication
The COL1A1 gene, located on chromosome 17 produces a component called a pro-alpha (I) chain which then combines with another pro-alpha (I) chain to make a type I procollagen molecule. Enzymes outside the cell process the triple-helical procollagen molecule. The molecule then arranges itself with other procollagen molecules into long, thin fibers that crosslink to one another. The result is the formation of very strong type I collagen fibers.
Alterations in DNA Replication and Gene Expression in Type I OI
90% of OI are caused by mutation in either COL1A1 or COL1A2. Over 400 mutations have been identified in the COL1A1 gene that codes for type I collagen. A nonsense mutation in the DNA leads to a premature termination codon, which results in translation stopping prematurely. This occurs due to a point mutation in the DNA leading to a stop codon being transcribed in the mRNA. A frameshift mutation that occurs during DNA replication shifts the frame one nucleotide to the right, so the same sequence of nucleotides encodes a different sequence of amino acids. The mRNA is transcribed in new groups of three nucleotides, causing the sequence of amino acids to be altered. The protein called for by these new codons will be nonfunctional. Both of these mutations result in the mutant COL1A1 gene producing fewer pro-alpha (I) chain proteins. The production of fewer pro-alpha1(I) chains causes cells to only produce half the normal amount of type I collagen, leading to Type I OI. Another mutation leads to deformities in type I collagen's triple helix's structure by replacing glycine with another amino acid in the G-X sequence, altering the carboxyl end of the amino acid chain. This point mutation occurs during DNA replication, resulting in an altered codon that is transcribed into RNA, which is then translated incorrectly, resulting in the substitution of another amino acid for glycine. This results in an abnormally structured type I collagen, as the fibril is unable to form a stable helical structure and crosslink properly with other fibrils, leading to Type I OI.

Phenotypic Impact of Type I OI
The genetic mutation causes the affected individual to have a lack of collagen proteins, which support and strengthen many tissues including cartilage, bone, tendon, skin, and sclera. These symptoms cause individuals to frequently fracture bones and have a gray- or blue-tinted sclera. Scoliosis, or curvature of the spine, dislocations and deformities of bones, hearing loss due to abnormal middle ear bones, short stature, decreased skin elasticity, and weakened teeth may occur.
Life Expectancy of OI
Osteogenesis Imperfecta
Due to OI being a genetic mutation, there is no cure, but there are treatments. Doctors suggest wearing orthotics to help support joints and prevent more fractures. Physical and occupational therapies help maintain range of motion and function. Surgery is the primary treatment for fractures. Surgeries include intramedullary rod placement, scoliosis correction, and in some circumstances, soft tissue surgery. Biophosphonate medication promotes bone growth. Pain medication can help control pain.
Works Cited
Type II OI is considered the most severe form of OI. Infants are born with short limbs, small chests, and soft skulls. Their legs are usually in a frog-leg position. They are born with deflated lungs, and multiple bone and vertebrae fractures. Also, there sclera are often very dark blue or gray. They are often born dead or die very soon after birth due to respiratory distress.
OI affects approximately 6-7 per 100,000 people worldwide. Type I OI accounts for 50% of all OI cases.
There are eight different types of OI.
Life expectancy is normal in Type I OI and from birth to a few weeks in Type II OI.
Type II
75% of mild types of OI, including Type I OI, have a mutation that occurs in the sperm or egg. This is important as germinal mutations in an egg or a sperm can be passed from parent to child if fertilization occurs. 25% of mild types of OI occur as a new somatic mutation in the early developing embryo. If a somatic cell is still dividing then the mutation will be cloned asexually within the developing embryo. Somatic mutations are not passed from parent to child. Most mild types of OI demonstrate an autosomal dominant inheritance pattern. An affected parent, who has one copy of an abnormal gene, would have a 50% chance of passing the gene on to a child, who would then have OI.
Mutation Occurs Mainly in Gametes
Type I
and Gene Expression
COL1A1: Normal Phenotype
Type I collagen, a fibrillar protein is present in the body's connective tissues, including bone, cartilage, tendon, sclera, and skin. When functioning properly, with the normal amount and normal functioning type I collagen fibers, it provides support and strength to the connective tissues of the body. Sclera are white and hearing is normal.
Phenotypic Abnormalities
in Type I OI
Symptoms and Challenges of Type I OI
Type I OI has mildest symptoms of all forms of OI. Bone fractures occur most commonly during childhood and adolescence due to trauma. Chronic pain may occur. People living with OI may have difficulty walking and climbing steps. A challenge during childhood and adolescence is avoiding even mild trauma that may cause fractures. Those with more severe forms of OI may have respiratory or cardiac abnormalities due to abnormal rib cages and scoliosis.
DNA Replication
In preparation for mitosis, COL1A1 replication takes place. Before the cell divides, the COL1A1 DNA must be copied. First, the DNA unwinds. Then, the two strands of the helix separate. DNA polymerase then binds complementary nucleotides on each strand, resulting in two double-stranded helices which are an exact copy of each other.
Gene Expression
The DNA of the COL1A1 gene is transcribed into RNA after RNA polymerase separates the two strands of DNA, allowing for their sequence of nucleotides to be transcribed into their corresponding nucleotides, forming RNA. The mRNA moves out of the nucleus to the cytoplasm where a codon, a three- nucleotide base sequence, is translated into a specific amino acid on ribosomes. The sequence of codons determines the amino acid sequence, forming a polypeptide chain. The amino acid sequence defines its primary structure and determines its tertiary structure. As translation occurs, the amino acid chain forms the secondary structure, either beta-pleated or alpha-helix shape, reinforced by hydrogen bonds. The secondary structure then folds and coils on itself to form the tertiary structure, type I collagen. The protein is functional once it is in its three-dimensional shape. Thus, through transcription, translation, and protein folding, the genotype in the DNA becomes the structural proteins which will express the organism's phenotype.
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