Download Stickler Syndrome

Stickler
Syndrome
COL2A1, COL11A1, COL11A2
Darron Fors &
Dr. Robert
Seegmiller
Brigham Young University
My Pedigree
Me
Symptoms within my family: Cleft palate, hearing loss,
osteoarthritis, hypermobile joints (double jointed), myopia
DNA Analysis Report
Patient Name
Fors, Gretta
Test Request
COL11A1
RESULTS:
Mutation
COL11A1Exon 61
Nucleotide
c.4537G>A
Amino Acid:
Gly995Ser
DNA sequencing of the COL11A1 gene revealed a c.4537G>A
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.
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
Collagen molecules involved
in Stickler Syndrome
 COL2A1 located on Chromosome 12
 COL11A1 located on Chromosome 1
 COL11A2 located on Chromosome 6
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
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 triplestranded, 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)
Components
of the
Extracellular
Matrix (ECM)
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
DNA Analysis
Patient Name
Report
Fors, Gretta
Test Request
COL11A1
RESULTS:
Mutation
COL11A1Exon
61
Nucleotide
c.4537G>A
Amino Acid:
Gly995Ser
DNA sequencing of the COL11A1
gene revealed a c.4537G>A
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.
COL2A1 Mutations
1
2
3
4
5
1
6
1.
2.
3.
4.
5.
6.
7.
8.
7
8
Stickler with cleft palate
Osteoarthritis with mild chondrodysplasia
Lethal chondrodysplasia (hypochondrogenesis)
Stickler with severe ophthalmopathy
Lethal chondrodysplasia (achondrogenesis II)
Severe chondrodysplasia (SED)
Severe chondrodysplasia (SED)
Severe chondrodysplasia (SED congenita)
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
Dmm and cho have a similar
phenotype
 Endochondral bone defect —> Dwarfism
 Micrognathia —>Tongue obstruction —>Cleft Palate
 Small thoracic space —> Pulmonary hypoplasia
My Personal Work
Normal (Wild) Type
Sedc Heterozygote
What’s 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