Transcript Achondroplasia

Achondroplasia:
Dwarfism
Kelly LaBarre
Clinical Features
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Achondroplasia literally means “without cartilage
formation.”
Presents clinically as a long narrow trunk with short
extremities, large head with frontal bossing,
hypoplasia of the midface, and trident configuration
of the hands.
An autosomal dominant disorder; a majority of cases
are sporadic, the result of a de novo mutation.
A de novo mutation is a new mutation that occurs in
a germ cell and is then passed on to an offspring.
FGFR3 Gene
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The gene affected is the Fibroblast Growth
Factor Receptor 3 gene, of FGFR3.
FGFR3 is located on chromosome 4, 4p16.3
Mutation
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There is a G to A transition at nucleotide 1138
of the coding sequence resulting in a gly380
to arg substitution.
Glycine is a basic side chain with its positive
charge stabilized by resonance.
Arginie is a nonpolar side chain consisting of
a single hydrogen atom.
GGG changes to AGG in the majority of the
cases of achondroplasia.
Protein Function
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These proteins play a role in several important
cellular processes, including regulation of cell
growth and division, determination of cell type,
formation of blood vessels, wound healing, and
embryo development.
FGFR3 is a transmembrane protein.
The FGFR3 protein is involved in the development
and maintenance of bone and brain tissue.
Researchers believe that this receptor regulates
bone growth by limiting the formation of bone from
cartilage in the long bones.
Conserved Domains
Most of the sections of the
conserved domains are
tyrosine kinases, which
are enzymes that can
transfer a phosphate
group from ATP to a
tyrosine residue in a
protein. This is important
because FGFR3 is a
transmembrane protein
that can interact outside
the cell to create a
cascade of events inside.
The remainder of the
conserved domains are
immunoglobulin chains.
3D Representation
This is an FGFR1 molecule, the
alpha chain is white and the
beta chain is blue. It has similar
function but different structure
than FGFR3. At the 380 position
it has a glutamine, which would
change to asparganine with the
point mutation, but this is not
what causes achondroplasia.
Aberrant Function
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The glycine to arginine switch in the protein
structure can create, obviously, large
problems.
Since the glycine side chain is so much
smaller and without a charge, the binding
sites and structure of the final protein are
altered.
glycine
arginine
Why?
The normal function of FGFR3 is to slow
down the formation of bone by inhibiting the
proliferation of chondrocytes, the cells that
produce cartilage. The mutation increases
the activity of FGFR3, severely limiting bone
growth. The mutant receptors actually work
better than the wild-type.
References
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GeneReviews
Editor-in-chief: Pagon, Roberta A. Associate editors: Cassidy, Suzanne B.; Bird, Thomas C.; Dinulos,
Mary Beth; Feldman, Gerald L.; Smith, Richard J.H.; Dolan, Cynthia R. Technical editor: Baskin, Patricia
K.
Seattle (WA): University of Washington; 1993-2006
Genes and disease.
Bethesda (MD): National Library of Medicine (US), NCBI.
Human Molecular Genetics 2 2nd ed.
Strachan, Tom and Read, Andrew P.
New York and London: Garland Science; c1999
http://www.ncbi.nlm.nih.gov/BLAST/
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
RCSB Protein Data Bank : http://www.rcsb.org/pdb/home/home.do