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Stone Man Syndrome: Causes & Cures

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Kayla O'Brien

on 10 December 2015

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Transcript of Stone Man Syndrome: Causes & Cures

Fibrodysplasia Ossificans Progressiva (FOP) or, more commonly known as Stone Man Syndrome
Genetic musculoskeleton condition in which muscle, tendons, & ligaments are progressively transformed into bone with the exception the tongue, diaphragm, & cardiac/smooth muscles
What is it?
ACVR1 Gene & Mutation:
Failed Treatments
General Information
Stone Man Syndrome: Causes & Cures
Retrieved from: http://www.uphs.upenn.edu/news/news_releases/apr06/briefing/factsinbrief_fop.pdf
Both images retrieved from: http://www.uphs.upenn.edu/news/news_releases/apr06/briefing/factsinbrief_fop.pdf
Affects 1 in 2 million people worldwide (extremely rare)
230 known cases in the US
Retrieved from: http://heilingoettergen564s15.weebly.com
Retrieved from: http://heilingoettergen564s15.weebly.com
: "activin A receptor, type 1"
missense mutation
on chromosome 2, which results in the 206th
amino acid to be swapped with
during translation
Leads to a
change of shape
ACVR1 receptor
in the
TGF-beta domain
of the
ALK2 protein
Retrieved from: http://flipper.diff.org/app/items/info/5995
ACVR1 Gene
Retrieved from: http://heilingoettergen564s15.weebly.com
X-Ray structure of ALK2 protein
ACVR1 Signaling Pathway
Retrieved from: http://www.nature.com/nrc/journal/v14/n10/images/nrc3811-f5.jpg
Progression of Ossification in FOP
Retrieved from: http://www.medscape.org/viewarticle/726287_2
Tripping & Falling
Current Research
Techniques Used:
Cre Lox Knock-In Mice
Genotyping of targeted ES cells & mice by a loss of allele assay
Digital PCR
Recombinant proteins & treatment of mice
Fluorescence activated cell sorting (FACS)
RT-PCR of exons 4-6
SDS-PAGE Gel Electrophoresis
Western Blotting/Immunoblotting
Current Treatments
Relevance to our
Biochemistry Course
Game of Thrones
(Fun Fact)
Retrieved from: http://gameofthrones.wikia.com/wiki/Greyscale
Should be diagnosed during neonatal period
No known effective medical therapy or cure available at this time
Corticosteroids & biphosphonates only used for flare-ups
RNA Interference
Early diagnosis, avoiding triggers, & proper treatment options help to improve quality of life
Triggers & Treatments
Retrieved from: www.ScienceTranslationalMedicine.org
Cre Lox Knock-In Mice
Digital PCR
Digital PCR Buffer components:
Biosearch assay (primer & probe mixture), QuantStudio 3D Digital PCR Master Mix, and water
96°C for 10 min, 39 cycles of 60° (2 min) and 98°C (30 s), followed by holding at 60° C (2 min), and stored at 10°C
Various primers were used
Used this technique to amplify exons 4-6 in order to detect RNA expression (protein production of ALK2)
RT-PCR Buffer components:
RNA isolated using QIazol Lysis Buffer (Qiagen) & Super Script III One-Step (Invitrogen)
cDNA synthesis & pre-denaturation:
1 cycle of: 45-60°C for 15-30 min; 94°C for 2 min
PCR amplification:
40 cycles of: 94°C (15 s); 55-66°C (30 s); 68°C (1 min)
Final Extension:
1 cycle of 68°C (5 min)
Primers Used:
Western Blotting/Immunoblotting
ALK2 activation in FOP
Retrieved from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481300/
Retrieved from: www.ScienceTranslationalMedicine.org
Initial Treatment
Retrieved from: www.ScienceTranslationalMedicine.org
Antibody Treatment
Retrieved from: www.ScienceTranslationalMedicine.org
GS: yellow
Kinase: grey
GS loop: purple
A loop: red
αC helix: blue
Arg Residues: green sticks
Retrieved from: http://flipper.diff.org/app/items/info/5995
Characteristics & Complications
Severe scoliosis
Hearing impairment
Scalp baldness
Menstrual irregularities
Premature menopause
Thoracic Insufficiency Syndrome
Cre-lox recombination is used to insert, remove, or translocate site specific base pairs in a gene sequence
Cre recombinase is an
which catalyzes a specific recombination between two
lox sites
flanking the gene of interest
Done through
homologous recombination
Gene of interest:
ACVR1 [R206H] mutant
Amino acid mutations
Different Levels of Protein Stucture & Characteristics
Binding of ligands
Techniques discussed in lecture:
Western Blot, PCR, RT-PCR
Also related to courses such as:
Molecular Biology
Developmental Biology
Topics Covered in Lecture
Emily Nunez & Kayla O'Brien
Full transcript