Identification of the Genetic Mutation that
Causes Fibrodysplasia Ossificans Progressiva
The FOP linkage region
• FOP is linked to a region of chromosome 2.
• A primary candidate gene within the linkage region was ACVR1
2p25 2p24 2p22 -
D2S1399 (148.0 Mb)
2p16 -
rs1020088 (150.6 Mb)
2p12 -
~23.9 Mb
2q12 2q14 2q22 2q24 2q31 2q32 2q34 2q36 2q37 Chromosome 2
D2S1238 (174.5 Mb)
ACVR1 (158.5 Mb)
Chromosomes contain DNA molecules (double he
Chromosomes contain
DNA molecules (double helix).
Information is DNA is given by the
Sequence/order of
4 types of nucleotides (A, C, G, T)
Our 23 pairs of chromosomes
contain 6 billion nucleotide
base pairs.
The human genome sequence
could fill a stack of books
as high as the
Washington Monument.
FOP is caused by a single nucleotide change in the
ACVR1 gene: G>A changes Arg206 to His206
• The identical heterozygous single
nucleotide polymorphism in the
ACVR1 gene at cDNA position 617
(c.617G>A) was identified in all
examined people with FOP.
• ACVR1 encodes a cell surface
receptor that receives information
from a set of bone-inducing growth
factors called bone morphogenetic
proteins (BMPs).
• A G>A change of one nucleotide
causes a substitution of a histidine in
place of an arginine amino acid.
Effect of the FOP mutation on ACVR1 protein
• Protein homology modeling examined putative structural changes caused by
the mutation:
¾ Modeling predicts a partial destabilization of the protein backbone.
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
• The FOP mutation forms a shorter side chain that alters the electrostatic potential
compared to the wild type ACVR1 protein, possibly either disrupting intramolecular
interactions that stabilize the ACVR1 protein or altering interactions between the GS
domain and other signaling pathway molecules
Summary
• Our previous and ongoing research on FOP has shown that BMP
signaling is changed/increased in FOP cells. The identification of
ACVR1 mutation is completely consistent with our previous work and
gives us a convergence of our different research strategies at the BMP
signaling pathway.
• The identification of a single specific amino acid change in FOP
provides a very specific target for developing treatments for FOP as
well as for other conditions of too much or too little cartilage/bone.