Presentation 1 Elly DeLaney

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Presentation 1Elly DeLaney

• Article Trummer, T., Brenner, R., et al. 2001.
  Recurrent mutations in the COL1A2 gene in
  patients with osteogenesis imperfecta. Clin.
  Genetics. 59338-343.

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Background

• Osteogenesis imperfecta (OI) is a genetic
  disorder characterized by bones that break easily
  for little or no cause. There are 4 main types
  of OI.

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Types of Osteogenesis Imperfecta

• Type I
• Most common and mildest type of OI.
• Bones predisposed to fracture.
• Most common and mildest type of OI.
• Bones predisposed to fracture.
• Most fractures occur before puberty.
• Normal or near-normal stature.
• Loose joints and low muscle tone.
• Sclera (whites of the eyes) usually have a
  blue, purple, or gray tint.
• Triangular face.
• Tendency toward spinal curvature.
• Bone deformity absent or minimal.
• Brittle teeth possible.
• Hearing loss possible, often beginning in early
  20s or 30s.
• Collagen structure is normal, but the amount is
  less than normal.

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Type II

• Most severe form.
• Frequently lethal at or shortly after birth,
  often due to respiratory problems. In recent
  years, some people with type 2 have lived into
  young adulthood.
• Numerous fractures and severe bone deformity.
• Small stature with underdeveloped lungs.
• Collagen is improperly formed
• Autosomal dominant type (the other 3 are
  autosomal recessive).

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Type III

• Bones fracture easily. Fractures often present at
  birth, and x-rays may reveal healed fractures
  that occurred before birth.
• Short stature.
• Sclera have a blue, purple, or gray tint.
• Loose joints and poor muscle development in arms
  and legs.
• Barrel-shaped rib cage.
• Triangular face.
• Spinal curvature.
• Respiratory problems possible.
• Bone deformity, often severe.
• Brittle teeth possible.
• Hearing loss possible.
• Collagen is improperly formed.

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Type IV

• Between Type I and Type III in severity.
• Bones fracture easily, most before puberty.
• Shorter than average stature.
• Sclera are white or near-white (i.e., normal in
  color).
• Mild to moderate bone deformity.
• Tendency toward spinal curvature.
• Barrel-shaped rib cage.
• Triangular face.
• Brittle teeth possible.
• Hearing loss possible.
• Collagen is improperly formed.

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• Variation in OI
• Estimated range of effected individuals
  20,000-50,000
• Diagnosis based mainly on clinical features, also
  biochemical and DNA tests

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Collagen

• Collagen is the most abundant protein in the
  body. It is composed of a triple helical
  structure in which glycine, a small amino acid,
  is essential in every third position for optimal
  folding.
• The genes COL1A1 and COL1A2 are responsible for
  collagen structure formation.

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The Patient

• Studies in this article were based on a female
  patient diagnosed with OI type III. During the
  1st three years of her life, 22 fractures
  occurred. She was implanted with rods in her
  femura and tibia and only 3 more fractures were
  noticed until she turned 10. Other symptoms
  demonstrated by the patient included
• -slightly blue sclera
• -severe dentinogenesis imperfecta

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PICP Test

• In the first test, the 10 year old patient was
  tested for serum levels of procollagen I
  C-terminal propeptide (PICP).
• The patients PICP levels were compared with 12
  other OI type III patients (ages 4-15) and 24
  control patients (ages 4-15).

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Results

• Patients Serum Levels 125 micro-grams per
  liter.
• Control Results 288 or 89 micro-grams per
  liter.
• OI type III patients 109 or 35 micro-grams
  per liter.

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Discussion

• Reduced serum levels in the patient indicate
  quantitative consequences of the underlying
  mutation for collagen type I biosynthesis.
• The fact that the patients serum levels were
  within the mean of other OI type III patient
  indicates that secretion of PICP could play an
  important role in determining clinical phenotypes
  of OI.

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Gene Sequence Variation

• The patients genes for COL1A1 and COL1A2 were
  examined for sequence variations.
• Evidence for mutation lead to the discovery of a
  Gly238Cys substitution due to a mutation in the
  COL1A2 gene. This proved to be the most
  N-terminal cystine substitution to date.
• All other mutations listed in the literature
  collated in the database of human collagen
  mutations were serine substitutions.

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Some recurrent COL1A1 mutations and their
clinical phenotype
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Some recurrent COL1A2 mutations and their
clinical phenotype
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Discussion

• An update shows that
• - In COL1A2 mutations, serine and cystine are
  predominant in glycine substitution. In
  addition, seven sites were identified as
  mutational hot spots.
• - In COL1A1 mutations, serine, cystine and
  arginine are predominant in glycin substitution.
  Also, 13 sites were identified as mutational hot
  spots.

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Significance of the Article

• Identified cystine as a glycine substitute (as
  opposed to serine)
• Raises questions as to why identical mutations in
  this genetically classical disorder lead to such
  phenotypic variability.

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Questions?
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References

• Trummer, T., Brenner, R., et al. 2001.
  Recurrent mutations in the COL1A2 gene in
  patients with osteogenesis imperfecta. Clin.
  Genetics. 59338-343
• Kuznetsova, N., McBride, D., Leikin, S. 2001.
  Osteogenesis imperfecta murine interaction
  between type I collagen homotrimers. J. Mol.
  Biol. 309807-815.
• Medical College of Wisconsin. Retrieved March 6,
  2002 at www.chorus.rad.mcw.edu
• Osteogenesis Imperfecta Foundation. Retrieved
  Jan. 31, 2002 at www.oif.org