CS 502: An Introduction to Computational Molecular Biology

1. CS 502: An Introduction to Computational Molecular Biology Postnatal neurodevelopmental disorders Meeting at the Synapse? Presenter: ANGELIKI PAPATHANASIOU UIN: 675777432 Original Author : Huda Y. Zoghbi Chicago 04/03/14

2. Synopsis Definitions Rett Syndrome (RTT) Autism Overlapping of RTT and Autism Future Scope

3. Definitions (1) Neurodevelopmental Disorders Brain functions Central Nervous System (CNS)

4. Definitions (2)The dendrites are responsible for the processing of information

5. Synopsis Definitions Rett Syndrome

6. Rett Syndrome (RTT) • Andreas Rett (cerebroatrophichyperammonemia) • Symptoms • Age 6-18 months • Females 1-10,000 (XX vs XY) • Verbal skills • Motor skills • X-linked Xq28 chromosome MeCP2 gene (methyl CpG binding protein 2) • One gene, many phenotypes

7. X - Chromosome X-linked Xq28 chromosome MeCP2 gene located on the 28 cytoband

8. The MeCP2 protein Bedogni et al, Neuroscience and Biobehavioral Reviews, 2014

9. Spatial and temporal distribution of MeCP2 during human development Zoghbi et al, Science, 302 (5646), 826-830, 2003

10. Mechanism of action MBD : Methyl-CpG-Binding Domain (key domain) Hydration of major groove of the methylated DNA

11. Cause of the disorder (1) De novo mutation Female XX, Male XY MeCP2 binds the 5-hydroxymethylcytosine (5hmC)-protein R133C mutation of MeCP2 inhibits the binding

12. MeCP2, 5hmC and chromatin

13. Cause of the Disorder (2) In the TRD the R270X and G273X A-T hook (proline-arginine-glycine-arginine-proline) Impairment in binding MeCP2 to DNA α-Thalassemia Mental Retardation X-Linked protein (ATRX)

14. Synopsis Definitions Rett Syndrome Autism

15. Autism Spectrum Disorder (1) • Discovered by Leo Kanner in 1940s • Family of disorders including • Aspergers • Pervasive developmental disorder not otherwise specified (PDD-NOS) • Autism

16. Autism Spectrum Disorder (2) Symptoms Intellectual disability motor coordination Language skills Physical health issues Age 6-14 months 1:166 male predominantly Small percentage excel in visual skills, math and art. Examples Temple Grandin, Einstein, Jacob Barnett  Johnson’s Theorem, Jacob Barnett TEDx Teen

17. Mechanism of Action • Many genes – One phenotype • Diagnosed on behavioral tests, not on biological markers • Abnormalities in the grey area of brain • MRI Brain enlargement • frontal lobe • dorsolateral prefrontal cortex (DLPFC) • Concordance rate is 90% for monozygotic twins • The cause of the disorder is yet to be discovered

18. Possible Cause of the Disorder (1) • chromosome 15 q11–q13 (Nullisomy, disomy, trisomy, and tetrasomy) • chromosome 16 q11.2 • mutations in the genes • SHANK2 and 3 • NRXN1 • NLGN3 • NLGN4

19. Possible Cause of the Disorder (2) • Chromosome 15q11–q13 • Paternally expressed many genes NDN, SNRPN-SNURF, C15orf2, MAGEL2, MKRN3 and snoRNAs • Maternally expressed • UBE3A (Ubiquitin-protein ligase E3A) – Angelman Syndrome • ATP10C

20. Possible Cause of the Disorder (3) The sex chromosome The neuroligin genes - de novo mutation, postsynaptic cell adhesion molecules NLGN-3 in the Xq13 NLGN-4 in the Yq11.2 Formation of a codon stops protein Maternal mutation R451C switches arginine to cysteine

21. Mice model Mice bearing homozygous deletions of the methyl-CpG–binding protein 1 (Mbd1) Mecp2-null mice same symptoms as Rett No dramatic changes in gene expression

22. Overlapping of RTT and Autism (1) • Common features • Age overlap: 6-18 months • Symptoms overlap: social and motor skills • Neurodevelopmental disorder targeting the brain and the CNS • Do they both meet at the synapse?

23. Overlapping of RTT and Autism (Rett) MECP2 mutations in 2 out of 68 females with an autistic disorder MeCP2 is not essential for initiating synaptogenesis Loss of learned skill leads to the belief that the ability of Rett patients to maintain or form new synapses is impaired.

24. Overlapping of RTT and Autism (Autism) • MECP2 mutations in individuals with ASD in the absence of RTT • NLGN-3 and -4 interact with β-neurexin • β-neurexinsinduce presynaptic differentiationin • immature cerebellar granule neurons • hippocampal neurons • Interactionwith neuroligin-1

25. Neuroligin mechanism in the synapse Zoghbi et al, Science, 302 (5646), 826-830, 2003

26. Overlapping of RTT and Autism Zoghbi et al, Science, 302 (5646), 826-830, 2003 Fewer dendrites in both syndromes

27. Bioinformatics (Herbert et al, 2006) • Autism and environmental genomics • Excel spreadsheet data from all autism genome scans to date • MySQL, usage of genomic databases • Environmental Genome Project • Inflammatory genes • Toxicogenomics • Pubmatrix to identify genes not studied previously • Golden pathway database to identify functional SNPs • 5300 genes analyzed • 135 genes from all three databases overlapped with autism linkage areas • 56 had not previously been studied (2005)

28. Statistics • After Sanger sequencing: • ANOVA • analyze the differences between group means and their associated procedures (eg. Gene expression in different brain regions) • t-test • Asses difference of two groups: healthy and autistic • difference between the gene expression or the DNA methylation

29. Future Scope • Epigenetics • Modifications regulate many genes • No effect on primary DNA sequencing • Usage of specific molecules • Open chromatin so that transcription can commence

30. Thank You