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Genetics of Stickler Syndrome
Noralane M. Lindor, M.D.
Department of Medical Genetics
Mayo Clinic, Rochester, Minnesota
Stickler, G. B.et al., Hereditary progressive
arthro-ophthalmopathy. Mayo Clin. Proc. 40:
433-455, 1965.
• …from a long experience at the Mayo Clinic with
multiple members of a kindred, described a new
dominant entity consisting of progressive myopia
beginning in the first decade of life and resulting in
retinal detachment and blindness. Affected persons
also exhibited premature degenerative changes in
various joints with abnormal epiphyseal development
and slight hypermobility in some.
From On Line Mendelian Inheritance
in Man (OMIM) 2007
Stickler Syndrome
• Genetic disorder of connective tissue
• Due to mutation in one of several genes
that encode different types of collagen
proteins that are important ingredients of
connective tissue of the eye, ear, cartilage,
and other tissues.
Construction of a body part
• Bricks
• Mortar
• Cells
• “Connective tissue”
What is mortar?
• Recipe of multiple
ingredients
• What is connective tissue?
• Recipe of multiple ingredients
•
•
•
•
•
Elastin
Fibrillin
Collagens
Tissue growth factors
Etc, etc, etc
Where does connective tissue
come from? How is it made?
• Secreted by the cells themselves based
on the genetic instructions within those
cells
Stickler Syndrome
• A clinical diagnosis–
• i.e., diagnosis does not depend on genetic
mutation being found
• Note: mutations in the genes causative of
some cases of Stickler Syndrome can also
cause other syndromes that are not
Stickler Syndrome
Stickler Syndrome:consider dx if
have findings in >2 categories
• Eye: congenital/early onset cataract, congenital
vitreous anomaly, rhegmatogenous retinal
detachment, myopia >-3 diopters
• Craniofacial: midface hypoplasia, bifid uvula,
cleft palate, micrognathia
• Ear: sensorineural or conductive hearing loss,
hypermobility of middle ear structures
• Joints: hypermobility, spondyloepiphyseal
dysplasia, early onset osteoarthritis
Edited Slide
• Clinical variability of Stickler syndrome
• Courtesy of: Journal
of Med Genetics
Metaphase spread of
chromosomes from one cell
Organization of human
chromosomes into a “karyotype”
46,XY
30,000 genes lined up single file
along the chromosomes
Chromosome 19
hundreds to
thousands of
different genes
on each
chromosome
Name and address of the 4
genes associated with Stickler
Syndrome
•
•
•
•
COL2A1
COL11A1
COL11A2
COL9A1
chromosome 12q13
chromosome 1p21
chromosome 6p21.3
chromosome 6q13
COL11A1
Stickler Syndrome gene locations
COL11A2
COL2A1
COL9A1
Individual collagen molecule is a triple
helix
Repetitve
sequence
Gly-X-Y
where X and
Y are
frequently
proline. It
forms a threestranded triple
helix
Edited Slide
Variation in the Vitreous
Phenotype of Stickler Syndrome
Can Be Caused by Different Amino
Acid Substitutions in the X Position
of the Type II Collagen Gly-X-Y
Triple Helix Variation in the
VitreousPhenotype of Stickler
Syndrome Can Be Caused by
Different Amino Acid Substitutions
in the X Position of the Type II
Collagen Gly-X-Y Triple Helix
COL2A1 exon 2 Mutations
American Journal of Human Genetics
Collagen genes vs collagen
fibers
• 40 different genes encoding at least 27
different types of collagens
• 22 different collagens seen in embryonic
or mature eye
• Only 6 different collagens seen in eye are
also present in joint cartilage. These
include Type II, V/XI, VI, IX, and XXVII.
• Best candidate genes for Stickler
syndrome
Collagen Type II
• Type II Collagen made up of three
chains of collagen encoded by COL2A1
– Causes Stickler Syndrome Type 1
– The most common type
– Eye finding most often persistence of vestigial
vitreous gel in retrolental space, border by
folded membrane, “membranous”
Collagen Type XI
• Type XI Collagen is made up of three
different strands encoded by:
– COL2A1
– COL11A1
– COL11A2
– Mutations in COL11A1 cause Stickler
Syndrome type II
– COL11A2 causes non ocular Stickler
Syndrome or Stickler Syndrome Type III
Genotype:Phenotype
• Mutations in COL11A1 have typical
Stickler eye findings– usually a beaded
pattern vitreopathy (rarely membranous)
“alpha 1 chain”
• COL11A2 not expressed in vitreous
(COL5A2 chain replaces it in Type XI
Collagen) therefore no eye problems in
Type II Stickler with COL11A2
mutations
“alpha 2 chain”
Collagen Type IX
• Type IX Collagen composed of one strand
each encoded by three different genes:
– COL9A1
– COL9A2
– COL9A3
– Mutations in COL9A1 can cause autosomal
recessive Stickler Syndrome– Type IV??
COL11A1
Stickler Syndrome gene locations
COL11A2
COL2A1
COL9A1
+
COL9A1
Stickler Syndrome Types I and
II: Autosomal Dominant
50-50 chance of passing gene to child
Does not matter if parent or child is male or female
Stickler Syndrome due to
COL9A1: autosomal recessive
Both parents carry one gene mutation but do not have Stickler
25% probability of each child having Stickler Syndrome
Child who inherits mutated gene from both mother and father have
Stickler Syndrome
First case in family: recessive
or de novo dominant mutation?
Putting all the genetics together
Sticklertype
Collagen Genes making 3
defect
strands in this
collagen
I
Type II COL2A1
II
Type XI COL2A1, COL11A1,
COL11A2
III non
Type XI COL2A1, COL11A1,
ocular
COL11A2
“IV”
Type IX COL9A1, COL9A2,
(recessive)
COL9A3
mutations
COL2A1
COL11A1
COL11A2
COL9A1
Genetic testing available,
moderately sensitive
•
•
•
•
COL2A1 27-80% mutations found
COL11A1 50-80%
COL11A2 unknown but available
COL9A1 unknown and unavailable
BUT……….!
Finding gene mutation not equal to
diagnosis of Stickler Syndrome
• Mutations in COL2A1 also cause:
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–
–
–
–
–
–
Achondrogenesis type II
Hypochondrogenesis
Spondyloepiphyseal dysplasia congenita
Spondyloepimetaphyseal dysplasia Studwick type
Kneist dysplasia
Spondyloperipheral dysplasia
Early-onset arthropathy
AD rhegmatogenous retinal detachment
Chondroectodermal
dysplasia
“Allelic disorder”: same gene,
different disorder
• Different types of disruption/mutation of a
gene affects the collagen production in
different ways
• The clinical picture may vary a lot
• Within a family, relatives have the same
disorder because they have the same
mutation, but severity can be quite
variable.
Furthermore….
• Mutations in COL11A1 can cause Marshall
Syndrome– hypoplasia of midface and
nasal bones and sinuses, myopia,
cataracts, deafness, short stature, early
arthritis, decreases hair and sweating
• Allelic or different disorder?
Furthermore….
• Mutations in COL11A2 can cause
– Autosomal recessive
otospondylometaepiphyseal dysplasia
– Weissenback-Zweymuller Syndrome
– Nonsyndromic sensorineural hearing loss
Furthermore…..
• Mutations in COL9A1 can cause a multiple
epiphyseal dysplasia: short trunked short
stature, multiple joints abnormal
Multiple epiphyseal dysplasia
(MED)
– mild short stature, irregularity of
multiple epiphyses, early arthritis
Genetic heterogeneity: about 10%
Due to mutations in COL9 genes
From European Journal of Human
Genetics (2007) 15, 150–154.
Stickler Syndrome Genetic Testing
– a choice, not a requirement
• Medically helpful? Would it tell
more than the family history?
– Diagnosis correct?
– Risk for eye complications?
– Reproductive risks: 50%? 25%? <1%?
– Prenatal diagnosis?
• Psychologically – do you want/need to
know?
• Cost? Insurance issues….