Stickler Syndrome

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Stickler Syndrome
COL2A1, COL11A1, COL11A2

• Darron Fors Dr. Robert Seegmiller
• Brigham Young University

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My Pedigree
Me
Symptoms within my family Cleft palate, hearing
loss, osteoarthritis, hypermobile joints (double
jointed), myopia
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DNA Analysis Report
Patient Name Fors, Gretta
Test Request COL11A1
RESULTS
Mutation COL11A1Exon 61 Nucleotide c.4537GgtA
Mutation COL11A1Exon 61 Amino Acid Gly995Ser
DNA sequencing of the COL11A1 gene revealed a
c.4537GgtA transition in exon 61. This mutation
converts a codon for a triple helical domain
glycine (GGT) to a serine (AGT). This mutation
will result in a phenotype consistent with
Stickler syndrome II. The patient is heterozygous
for this mutation.
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Human Chromosomes

• Each cell in human body has 23 pair of
  chromosomes in the nucleus
• Number of genes in our chromosomes is about
  30,000
• Genes are segments of DNA, each of which
  ultimately code for a protein
• These proteins and other molecules produced by
  genes determine the traits of a living organism

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Collagen molecules involved in Stickler Syndrome

• COL2A1 located on Chromosome 12
• COL11A1 located on Chromosome 1
• COL11A2 located on Chromosome 6

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Protein Synthesis

• A section (gene) of DNA unwinds and the
  nucleotides of the DNA provide the pattern for
  making the messenger RNA (mRNA).
• mRNA is used as instructions to piece together
  amino acids that form proteins
• Collagen is one of these proteins

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Functions of COL11A1 Gene

• The COL11A1 gene provides instructions for making
  one component of type XI collagen, called the
  pro-alpha1(XI) chain. Type XI collagen adds
  structure and strength to the connective tissues
  that support the body's muscles, joints, organs,
  and skin. Type XI collagen is normally found in
  cartilage. Type XI collagen is also part of the
  clear gel that fills the eyeball (the vitreous),
  the inner ear, and the center portion of the
  discs between the vertebrae in the spine (nucleus
  pulposus).
• The pro-alpha1(XI) chain combines with two other
  collagen chains (pro-alpha2(XI) and
  pro-alpha1(II)) to form a procollagen molecule.
  These triple-stranded, ropelike procollagen
  molecules are then processed by enzymes in the
  cell. Once processed, procollagen molecules leave
  the cell and arrange themselves into long, thin
  fibrils that link to one another (cross-link) in
  the spaces around cells. The cross-linkages
  result in the formation of very strong mature
  type XI collagen fibers.
• Type XI collagen also helps maintain the spacing
  and diameter of type II collagen fibrils. Type II
  collagen is an important component of the eye and
  mature cartilage tissue. The size and arrangement
  of type II collagen fibrils is essential for the
  normal structure of these tissues.
• (from the NIH Genetics Reference)

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Components of the Extracellular Matrix (ECM)
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Importance of types II/XI collagen

• Collagen II
• Principal fibrillar component of cartilage ECM
• Provides cohesive properties of cartilage
• Collagen XI
• Essential for normal formation of collagen
  fibrils
• Responsible for spatial organization of growth
  plate
• Mutations
• In genes encoding polypeptide subunits of
  collagen II and XI are responsible for several
  chondrodysplasias

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DNA Analysis Report
Patient Name Fors, Gretta
Test Request COL11A1
RESULTS
Mutation COL11A1Exon 61 Nucleotide c.4537GgtA
Mutation COL11A1Exon 61 Amino Acid Gly995Ser
DNA sequencing of the COL11A1 gene revealed a
c.4537GgtA transition in exon 61. This mutation
converts a codon for a triple helical domain
glycine (GGT) to a serine (AGT). This mutation
will result in a phenotype consistent with
Stickler syndrome II. The patient is heterozygous
for this mutation.
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COL2A1 Mutations
1
2
3
4
5
1
7
6
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1. Stickler with cleft palate 2. Osteoarthritis
with mild chondrodysplasia 3. Lethal
chondrodysplasia (hypochondrogenesis) 4.
Stickler with severe ophthalmopathy 5. Lethal
chondrodysplasia (achondrogenesis II) 6. Severe
chondrodysplasia (SED) 7. Severe
chondrodysplasia (SED) 8. Severe
chondrodysplasia (SED congenita)
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What is being done in the lab?

• It starts with establishing mouse models for
  study
• Mouse models at Brigham Young University
• Disproportionate micromelia(Dmm)
• Micromelia (dwarfism)
• COL2A1 mutation
• chondrodysplasia(cho)
• Chondro- (cartilage), dysplasia- (abnormality)
• COL11A1 mutation
• spondlyoepiphysealdysplasiacongenita(sedc)
• Spondylo- (bones of the spine), epiphyses- (ends
  of long bones), dysplasia- (abnormality),
  congenita- (from birth)
• COL2A1 mutation

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Dmm and cho have a similar phenotype

• Endochondral bone defect gt Dwarfism
• Micrognathia gtTongue obstruction gtCleft Palate
• Small thoracic space gt Pulmonary hypoplasia

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My Personal Work
Normal (Wild) Type
Sedc Heterozygote
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Whats the point?

• Finding anomalies between the wild type and
  mutant types
• Points us in the right direction to address the
  problem
• Identification of the problem at the molecular
  level paves the way for discovery of drug
  treatments
• Understanding the roles of specific genes and
  their interaction with other genes
• Essential for possible gene therapy used in the
  future