2010 Conference - Basic Boot Camp for Translation

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Phelan-McDermid Syndrome

Biology Basicsfor the Family

Randy Riddle

Co-Chair, Research Support

Committee



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



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´



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´





PMS Deletions (as of 2003)

56 Cases

Uniform Distribu

tion

Study Inconclusive

± Low correlation of size

to symptoms



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´



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



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´



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)



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!



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



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 =



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



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



What do carpenters do with 2x4¶s?

Attach to the foundation

Attach to each other Hold

Pipes In Place

Hold Electrical Outlets



What do PSD¶s do with SHANK3¶s?

Attach to the foundation

Attach to each other Hold

Pipes In Place

Hold Electrical

Wiring



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

=



What happens without enough

SHANK3?



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



SHANK3 in the PSD

=



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



How will we find out?

Knockout Mouse

Induced Pluripotent Stem Cells

Registry and Repository



What will we do when we find out?

Possibilities: ± Effective Drug Treatments

± Effective/Focused Therapy Methods

± Gene Therapy (Maybe?)

Documents

2010 Conference - Basic Boot Camp for Translation