2010 Conference - Basic Boot Camp for Translation
-
Upload
sarath-bethapudi -
Category
Documents
-
view
222 -
download
0
Transcript of 2010 Conference - Basic Boot Camp for Translation
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 1/24
Phelan-McDermid Syndrome
Biology Basicsfor the Family
Randy Riddle
Co-Chair, Research Support
Committee
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 2/24
Over view
The Chromosome
The 22q13 Deletion
SHANK3 Gene and Protein Hope for the Future Walkaways
1. Your Genome is an
Encyclopedia
2. The Neuron is a House
3. SHANK3 is a 2x4
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 3/24
What is a Chromosome? A very, very, very large
organic molecule
Like H2O, but bigger C10,000,000H100,000,000N10,000,000O50,000,000P10,000,000
Spelling out a 4-letter code
A C T G: known as ³Base Pairs´
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 4/24
The 22nd Chromosome 2nd smallest chromosome (should have been #21)
51 Million letters (base pairs)
The very first human chromosome decoded (1999)
How many genes are on chromosome 22?
± 522 (roughly 2% of the total)
³Encyclopedia of me´
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 5/24
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 6/24
PMS Deletions (as of 2003)
56 Cases
Uniform Distribu
tion
Study Inconclusive
± Low correlation of size
to symptoms
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 7/24
What Does the
4-Letter Code
Say? A C T G
How much can you
say with a 4 letter alphabet?
± Answer: Not much
Solution: Speak in ³3-
letter syllables´
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 8/24
Learning to Read Words
3-letter syllables
are used to make
words called
Amino Acids
There are 22 of
these ³words´
used in our genes
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 9/24
Feature Articles
Complete concepts are communicated infeature articles, which we call ³genes´.
Tell ³someone´ how to make ³something´.
SHANK3 is one such feature article. ± Five paragraphs long
± Near the end of Volume 22 of the ³Encyclopedia of Me´
± Codes for your body¶s equivalent of a ³2x4´
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 10/24
What does the SHANK3 article
say? MDGPGASAVV VRVGIPDLQQ TKCLRLDPAA PVWAAKQRVL CALNHSLQDA LNYGLFQPPS RGRAGKFLDEERLLQEYPPN LDTPLPYLEF RYKRRVYAQN LIDDKQFAKL HTKANLKKFM DYVQLHSTDK V ARLLDKGLDPNFHDPDSGE CPLSLAAQLD NATDLLKVLK NGGAHLDFRT RDGLTAVHCA TRQRNAAALT TLLDLGASPDYKDSRGLTPL YHSALGGGDA LCCELLLHDH AQLGITDENG WQEIHQACRF GHVQHLEHLL FYGADMGAQN ASGNTALHIC ALYNQESCAR VLLFRGANRD VRNYNSQTAF QV AIIAGNFE LAEVIKTHKD SDVVPFRETPSYAKRRRLAG PSGLASPRPL QRSASDINLK GEAQPAASPG PSLRSLPHQL LLQRLQEEKD RDRDADQESNPLAGRAG QSKISEPGAP RSCIRIRARF PAPPAPPAPP PRGPKRKLYS AVPGRKFIAV KAHSPQGEGEIPLHRGEAVK VLSIGEGGFW EGTVKGRTGW FPADCVEEVQ MRQHDTRPET REDRTKRLFR HYTVGSYDSLTSHSDYVIDD KV AVLQKRDH EGFGFVLRGA KAETPIEEFT PTPAFPALQY LESVDVEGV A WRAGLRTGDFLIEVNGVNVV KVGHKQVV AL IRQGGNRLVM KVVSVTRKPE EDGARRRAPP PPKRAPSTTL TLRSKSMTAELEELASIRRR KGEKLDEMLA AAAEPTLRPD IADADSRAAT VKQRPTSRRI TPAEISSLFE RQGLPGPEKLPGSLRKGIPR TKSVGEDEKL ASLLEGRFPR STSMQDPVRE GRGIPPPPQT APPPPPAPYY FDSGPPPAFSPPPPPGRAYD TVRSSFKPGL EARL GAGAAG LYEPGAALGP LPYPERQKRA RSMIILQDSA PESGDAPRPPPAATPPERPK RRPRPPGPDS PYANLGAFSA SLFAPSKPQR RKSPLVKQLQ VEDAQERAAL AVGSPGPGGGSFAREPSPTH RGPRPGGLDY GAGDGPGLAF GGPGPAKDRR LEERRRSTVF LSVGAIEGSA PGADLPSLQPSRSIDERLLG TGPTAGRDLL LPSPVSALKP LVSGPSLGPS GSTFIHPLTG KPLDPSSPLA LALAARERAL ASQAPSRSPT PVHSPDADRP GPLFVDVQAR DPERGSLASP AFSPRSPAWI PVPARREAEK VPREERKSPEDKKSMILSVL DTSLQRPAGL IVVHATSNGQ EPSRLGGAEE ERPGTPELAP APMQSAAV AE PLPSPRAQPPGGTPADAGPG QGSSEEEPEL VFAVNLPPAQ LSSSDEETRE ELARIGLVPP PEEFANGVLL ATPLAGPGPSPTTVPSPASG KPSSEPPPAP ESAADSGVEE ADTRSSSDPH LETTSTISTVSSMSTLSSES GELTDTHTSF ADGHTFLLEK PPVPPKPKLK SPLGKGPVTF RDPLLKQSSD SELMAQQHHA ASAGLASAAG PARPRYLFQR
RSKLWGDPVE SRGLPGPEDD KPTVISELSS RLQQLNKDTR SLGEEPVGGL GSLLDPAKKS PIAAARCRSPMVGLRLFSSL GELSSISAQR SPGGPGGGAS YSVRPSGRYP V ARRAPSPVK PASLERVEGL GAGAGGAGRPFGLTPPTILK SSSLSIPHEP KEVRFVVRSV SARSRSPSPS PLPSPASGPG PGAPGPRRPF QQKPLQLWSKFDVGDWLESI HLGEHRDRFE DHEIEGAHLP ALTKDDFVEL GVTRVGHRMN IERALRQLDG
1731 Words (Amino Acids)
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 11/24
Paragraphs
In genes, the paragraphs of the article arecalled ³domains´.
Example: SAM is one paragraph
± ³Sterile Alpha Motif´
64 Words
PSTWSVEAVVLFLKQTDPLALCPLVDLFRSHEID
GKALLLLTSDVLLKHLGVKLGTAVKLCYYIDRLKQ
This SAM is
Much friendlier!
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 12/24
What does SAM look like?
Source: ³An Architectural Framework That
May Lie at the Core of the Postsynaptic Density ,́Science Magazine 27 Jan 2006, Baron et. Al.
We have some clues:
± SAM makes microscopic sheets
like a crocheted afghan
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 13/24
PPPPPP
SHANK3 in Concept
5 Paragraphs ± Ankyrin Repeats
± SH3
± PDZ ± Proline-Rich Region
± SAM
A
N
K
A
N
K
A
N
K
A
N
K
A
N
K
A
N
KPDZSH3 =
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 14/24
What does SHANK3 really look
like?Making a 2x4 is a 4-step process:
1. The Librarian makes a copy of the article.
2. The copy is shoved out a mail
slot.3. The manufacturer makes a
string of yarn.
4. The string of yarn folds itself intoa 3D structure.
DNA
Polymerase
Nuclear Pore
Ribosome
Protein
Folding
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 15/24
Where is SHANK3 ³Made´?
What is it used for there?
± ³Scaffold Protein´ in the Neuron
± If you have experience inconstruction, think ³Framing Protein´
Source: www.genecards.org
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 16/24
What do carpenters do with 2x4¶s?
Attach to the foundation
Attach to each other Hold
Pipes In Place
Hold Electrical Outlets
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 17/24
What do PSD¶s do with SHANK3¶s?
Attach to the foundation
Attach to each other Hold
Pipes In Place
Hold Electrical
Wiring
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 18/24
PSD is ³Post-Synaptic Density´ It is the ³receive´ end of the synapse
Synapse is a small physical feature of a single Neuron
± Lines blur between chemistry and electricity
You have about 100 trillion
Source: Wikipedia.com ,´Chemical Synapse´
~1 micrometer
If SHANK3 = 2x4, PSD = House
=
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 19/24
What happens without enough
SHANK3?
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 20/24
The Neuron is the Neighborhood Neurons are Single Cells ± But Some are VERY LONG
± Nucleus, cell wall, etc.
± Roughly equivalent to a strand of hair
3 Things to Know
± Synapse: Where 2 Neurons Touch (almost)
± Electrical Signals ± Chemical Reactions
You have about 100 billion
± ~1,000 synapses each
Source: Wikipedia.com ,´Neuron´
5-100 micrometers(hair is 70 micrometers)
Up to a meter long
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 21/24
SHANK3 in the PSD
=
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 22/24
What has THIS got to do with US?
So our kids are missing a few pages out of one copy of Volume 22, ± Why does this matter if we have 2 copies of each book?
We don¶t know
So 22q13 contains lots of genes besides SHANK3, ± Do any of those matter?
We don¶t know
So SHANK3 is a scaffold protein in the synapse, ± Why does this make our kids have trouble talking?
We don¶t know
So SHANK3 is found lots of other places than synapse,
± What do those other places use 2x4¶s for? We don¶t know
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 23/24
How will we find out?
Knockout Mouse
Induced Pluripotent Stem Cells
Registry and Repository
8/8/2019 2010 Conference - Basic Boot Camp for Translation
http://slidepdf.com/reader/full/2010-conference-basic-boot-camp-for-translation 24/24
What will we do when we find out?
Possibilities: ± Effective Drug Treatments
± Effective/Focused Therapy Methods
± Gene Therapy (Maybe?)