Phelan-McDermid Syndrome

Biology Basics
for the Family

Randy Riddle
Co-Chair, Research Support
Committee
 Overview
• 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 “Base Pairs”
 The 22 Chromosomend

• 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)

“Encyclopedia of me”
 The 22q13 Deletion
• The 22q13 Region = 14 Million Base Pairs
– ~270 Genes (per Human Genome #19, Aug 2009)
The genes of 22q13.33
– 1. MGC70863 – 16. LMF2 – 29. PANX2
– 2. RABL2B – 17. MIOX – 30. MOV10L1
– 3. ACR – 18. ADM2 – 31. MLC1
– 4. SHANK3 – 19. SBF1 – 32. IL17REL
– 5. ARSA
– 20. SAPS2 – 33. PIM3
– 6. IB2
– 7. CHKB – 21. FAM116B – 34. CRELD2
– 8. CHKB-CPT1B – 22. PLXNB2 – 35. ALG12
– 9. CPT1B – 23. MAPK11 – 36. LOC100129225
– 10. LOC644186 – 24. MAPK12 – 37. ZBED4
– 11. KLHDC7B
– 25. HDAC10 – 38. LOC100132706 3.6 Mb, 93 genes
– 12. LOC440836
– 13. ECGF1 – 26. TUBGCP6 – 39. BRD1 3.1 Mb, 74 genes
– 14. SCO2 – 27. SELO – 40. LOC100129647
– 15. NCAP-H2 – 28. TRABO 4.5 Mb, 56 genes
– 41. LOC100129944
– 42. C22orf34 1.2 Mb, 4 genes
1.4 Mb, 43 genes
– 43. FLJ44385
 PMS Deletions (as of 2003)

• 56 Cases
• Uniform Distribution
• Study Inconclusive
– Low correlation of size
to symptoms
What Does the
4-Letter Code
Say?
• ACTG
• How much can you
say with a 4 letter
alphabet?
– Answer: Not much
• Solution: Speak in “3-
letter syllables”
 Learning to Read Words
• 3-letter syllables
are used to make
words called
Amino Acids
• There are 22 of
these “words”
used in our genes
 Feature Articles
• Complete concepts are communicated in
feature articles, which we call “genes”.
• Tell “someone” how to make “something”.
• SHANK3 is one such feature article.
– Five paragraphs long
– Near the end of Volume 22 of the “Encyclopedia of Me”
– Codes for your body’s equivalent of a “2x4”
 What does the SHANK3 article
say?
• MDGPGASAVV VRVGIPDLQQ TKCLRLDPAA PVWAAKQRVL CALNHSLQDA LNYGLFQPPS RGRAGKFLDE
ERLLQEYPPN LDTPLPYLEF RYKRRVYAQN LIDDKQFAKL HTKANLKKFM DYVQLHSTDK VARLLDKGLD
PNFHDPDSGE CPLSLAAQLD NATDLLKVLK NGGAHLDFRT RDGLTAVHCA TRQRNAAALT TLLDLGASPD
YKDSRGLTPL YHSALGGGDA LCCELLLHDH AQLGITDENG WQEIHQACRF GHVQHLEHLL FYGADMGAQN
ASGNTALHIC ALYNQESCAR VLLFRGANRD VRNYNSQTAF QVAIIAGNFE LAEVIKTHKD SDVVPFRETP
SYAKRRRLAG PSGLASPRPL QRSASDINLK GEAQPAASPG PSLRSLPHQL LLQRLQEEKD RDRDADQESN
PLAGRAG QSKISEPGAP RSCIRIRARF PAPPAPPAPP PRGPKRKLYS AVPGRKFIAV KAHSPQGEGE
IPLHRGEAVK VLSIGEGGFW EGTVKGRTGW FPADCVEEVQ MRQHDTRPET REDRTKRLFR HYTVGSYDSL
TSHSDYVIDD KVAVLQKRDH EGFGFVLRGA KAETPIEEFT PTPAFPALQY LESVDVEGVA WRAGLRTGDF
LIEVNGVNVV KVGHKQVVAL IRQGGNRLVM KVVSVTRKPE EDGARRRAPP PPKRAPSTTL TLRSKSMTAE
LEELASIRRR KGEKLDEMLA AAAEPTLRPD IADADSRAAT VKQRPTSRRI TPAEISSLFE RQGLPGPEKL
PGSLRKGIPR TKSVGEDEKL ASLLEGRFPR STSMQDPVRE GRGIPPPPQT APPPPPAPYY FDSGPPPAFS
PPPPPGRAYD TVRSSFKPGL EARL GAGAAG LYEPGAALGP LPYPERQKRA RSMIILQDSA PESGDAPRPP
PAATPPERPK RRPRPPGPDS PYANLGAFSA SLFAPSKPQR RKSPLVKQLQ VEDAQERAAL AVGSPGPGGG
SFAREPSPTH RGPRPGGLDY GAGDGPGLAF GGPGPAKDRR LEERRRSTVF LSVGAIEGSA PGADLPSLQP
SRSIDERLLG TGPTAGRDLL LPSPVSALKP LVSGPSLGPS GSTFIHPLTG KPLDPSSPLA LALAARERAL
ASQAPSRSPT PVHSPDADRP GPLFVDVQAR DPERGSLASP AFSPRSPAWI PVPARREAEK VPREERKSPE
DKKSMILSVL DTSLQRPAGL IVVHATSNGQ EPSRLGGAEE ERPGTPELAP APMQSAAVAE PLPSPRAQPP
GGTPADAGPG QGSSEEEPEL VFAVNLPPAQ LSSSDEETRE ELARIGLVPP PEEFANGVLL ATPLAGPGPS
PTTVPSPASG KPSSEPPPAP ESAADSGVEE ADTRSSSDPH LETTSTISTV SSMSTLSSES GELTDTHTSF
ADGHTFLLEK PPVPPKPKLK SPLGKGPVTF RDPLLKQSSD SELMAQQHHA ASAGLASAAG PARPRYLFQR
RSKLWGDPVE SRGLPGPEDD KPTVISELSS RLQQLNKDTR SLGEEPVGGL GSLLDPAKKS PIAAARCRSP
MVGLRLFSSL GELSSISAQR SPGGPGGGAS YSVRPSGRYP VARRAPSPVK PASLERVEGL GAGAGGAGRP
FGLTPPTILK SSSLSIPHEP KEVRFVVRSV SARSRSPSPS PLPSPASGPG PGAPGPRRPF QQKPLQLWSK
FDVGDWLESI HLGEHRDRFE DHEIEGAHLP ALTKDDFVEL GVTRVGHRMN IERALRQLDG
• 1731 Words (Amino Acids)
 Paragraphs
• In genes, the paragraphs of the article are
called “domains”.
• Example: SAM is one paragraph
– “Sterile Alpha Motif”
• 64 Words
• PSTWSVEAVVLFLKQTDPLALCPLVDLFRSHEID
GKALLLLTSDVLLKHLGVKLGTAVKLCYYIDRLKQ

This SAM is
Much friendlier!
 What does SAM look like?
• We have some clues:
– SAM makes microscopic sheets
• like a crocheted afghan

Source: “An Architectural Framework That

May Lie at the Core of the Postsynaptic Density”,
Science Magazine 27 Jan 2006, Baron et. Al.
 SHANK3 in Concept
• 5 Paragraphs
– Ankyrin Repeats
– SH3
– PDZ
– Proline-Rich Region
– SAM
AAAAAA
NNNNNN
KKKKKK
SH3 PDZ PPPPPP =
 What does SHANK3 really look
like?
Making a 2x4 is a 4-step process:
1. The Librarian makes a copy of
the article.
DNA
2. The copy is shoved out a mail Polymerase
slot.
3. The manufacturer makes a
string of yarn.
4. The string of yarn folds itself into
a 3D structure.
Protein Nuclear Pore
Folding

Ribosome
 Where is SHANK3 “Made”?

• What is it used for there?

– “Scaffold Protein” in the Neuron
– If you have experience in
construction, think “Framing 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
 If SHANK3 = 2x4, PSD = House
• PSD is “Post-Synaptic Density”
• It is the “receive” 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

~1 micrometer
=

Source: Wikipedia.com ,”Chemical Synapse”

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 Up to a meter long
– Synapse: Where 2 Neurons Touch (almost)
– Electrical Signals
– Chemical Reactions
• You have about 100 billion
– ~1,000 synapses each
5-100 micrometers
(hair is 70 micrometers)

Source: Wikipedia.com ,”Neuron”

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?)