Transcript Spinal Muscular Atrophy SMN1

Spinal Muscular Atrophy
SMN1
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Gubitz et al. The SMN Complex. Experimental Cell Research(2004) 296: 51-56
Medline Plus (2009) Spinal Muscular Atrophy
retrieved Feb 3, 2009 from: http://www.nlm.nih.gov/medlineplus/spinalmuscularatrophy.html
Billy Baader - Genetics 677
What is SMA?
• Neuromuscular Disease
• Inactivated Muscle Communication
Weak and eventually atrophied muscles
• Death is inevitable
• Characterized by time of onset and
severity
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Severity and Statistics
Type I Acute - <6 months after birth
Type II Intermediate - age 6 - 18 months
Type III Mild - 18 months - early adulthood
Type IV Adult Onset - adulthood
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1 in 35-40 Americans are carriers
Retrieved from: http://www.fsma.org/FSMACommunity/understandingsma
1 in 10,000 infants effected
Most deadly recessive genetic disease among infants
Cause of SMA - SMN1
• Deletion or a mutation of the SMN1
gene leads to SMA
• SMN1 encodes Survival of motor
neuron protein 1
• Functions in snRNP biogenesis and
mRNA processing
• Problem is in the anterior horn cells
Spinal Cord
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Retrieved from: http://student.britannica.com/comptons/art-66123/Section-of-a-spinal-cord
SMN1 Gene + Protein
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Spinal Muscular Atrophy Foundation (2009) About SMA
retrieved from: http://www.smafoundation.org/index.php?option=com_faq&Itemid=32&Itemid=32
• 28,050 base pairs
• 294 aa
• 9 exons
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• SMN2
Retrieved from: http://www.ebi.ac.uk/msd-srv/msdlite/atlas/visualization/1g5v.html
SMN Complex
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Gubitz et al. The SMN Complex. Experimental Cell Research(2004) 296: 51-56
Protein Network (Homo Sapiens)
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Retrieved from: http://string.embl.de/newstring_cgi/show_network_section.pl
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Retrieved from: http://string.embl.de/newstring_cgi/show_network_section.pl
Protein Network (Mus
Musculus)
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Retrieved from: http://string.embl.de/newstring_cgi/show_network_section.pl
Phylogeny
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Retrieved from: http://www.phylogeny.fr/
Homologs
Homologs
1. SMN1, Pan troglodytes (Chimpanzee)
survival of motor neuron 1, telomeric
Percent Identity:
DNA: 99.4
Protein:100
2. SMN, Canis lupus familiaris (Dog)
survival motor neuron
DNA: 90.8
Protein: 89.4
3. SMN, Bos taurus (Cow)
survival motor neuron
DNA: 88.2
Protein: 85.2
4. Smn1, Mus musculus (Mouse)
survival motor neuron 1
DNA: 83.5
Protein: 83.3
5. Smn1, Rattus norvegicus (Rat)
survival motor neuron 1
DNA: 82.1
Protein: 81.2
6. SMN, Gallus gallus (Rooster)
survival motor neuron
DNA: 67.1
Protein: 64.8
7. smn1, Danio rerio (Zebrafish)
survival motor neuron 1
DNA: 61.2
Protein: 59.0
Protein Domain: Tudor
Protein-protein
Interactions
RNA metabolism
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Not fully
understood
Retrieved from: Huang, Y. et al. (2006) Science. 312(5774): 748-51. PDB: 2GFA
Mystery of SMA
Why low levels of SMN protein in the cells of SMA patients
lead to the specific loss of motor neurons remains a central
question in this field.
SMN may be involved in the transport of specific mRNA
molecules in motor axon.
However, whether the clinical symptoms of SMA are caused
by deficiencies in functions of SMN that are specific to the
motor neuron or common to all cells but at higher demand
in this cell type must still be resolved.
Future Possibilities
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Yeast Two Hybrid
– Neural vs. other tissues
Retrieved from:
http://www.bio.davidson.edu/COURSES/genomics/2005/Durnbaugh/home.ht
Microarrays of gene expression in
different tissues
Mice should be good model organisms to
research SMA
Questions
References
1. Spinal Muscular Atrophy Foundation (2009) About SMA retrieved
Feb 3, 2009 from:
http://www.smafoundation.org/index.php?option=com_faq&Itemi
d=32&Itemid=32
2.Medline Plus (2009) Spinal Muscular Atrophy retrieved Feb 3,
2009 from:
http://www.nlm.nih.gov/medlineplus/spinalmuscularatrophy.html
3.eMedicine (2009) Spinal Muscular Atrophy retrieved Feb 3, 2009
from: http://emedicine.medscape.com/article/1181436-overview
4.Fight SMA What is Spinal Muscular Atrophy retrieved Feb 3,
2009 from: http://www.fightsma.org/index.php?what_is_sma