Achondroplasia: Dwarfism

1
Achondroplasia Dwarfism

• Kelly LaBarre

2
Clinical Features

• 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.

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FGFR3 Gene

• The gene affected is the Fibroblast Growth Factor
  Receptor 3 gene, of FGFR3.
• FGFR3 is located on chromosome 4, 4p16.3

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Mutation

• 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.

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Protein Function

• 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.

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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.
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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.
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Aberrant Function

• 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
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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.

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References

• 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?dbO
  MIM
• RCSB Protein Data Bank http//www.rcsb.org/pdb/h
  ome/home.do