The Impact of the Williams Syndrome Mutations on Neural
Organization and Brain Function: A Window into Social Cognition

James S. McDonnell Foundation Collaborative Activity Award:
Bridging Brain, Mind and Behavior
January 1, 2002 -- January 1, 2005




The Genetic and Neural Basis of Social Cognition:
Evidence from Williams Syndrome and Non-Human Primates


Three genes, CYLN2, GTF2IRD1 and GTF2I, located in the Williams region of chromosome 7, may be responsible for the hypersociability that is so evident in the Williams syndrome phenotype. Little is known about the function of these genes and when or where these genes are expressed. To address these questions, in Projects 1 and 2 we will examine and parse out the social behavior of Williams individuals with full deletions compared to those with smaller deletions and to normal controls to examine what aspects of social behavior are affected, integrated with the molecular genetic analyses of these genes in Williams. In this proposal, we will use the nonhuman primate model to more effectively study direct links between these specific genes and social cognition. The expression of these genes will also provide presumptive evidence that the brain regions in which they are located have a role in the regulation of social cognition.


We will use metabolic and functional brain imaging technology in Project 4 to determine which brain regions are more activated to social stimuli in the classical Williams patient compared to the short form of the deletion as an indicator of brain regions associated with the hypersocial behavior of the typical Williams subject. We would predict that the brain regions preferentially activated in the full deletion Williams subject might be the same as the regions demonstrating differential expression for CYLN2, GTF2IRD1 or GTF2I in the monkey brain. As initial stages in developing a nonhuman primate model of Williams syndrome, in Projects 3 and 5, we will search for rhesus monkeys that naturally display either hypersocial or hyposocial behavior and examine their genetic composition. Finally, in Project 6 we will use a recently developed molecular/genetic technique to transiently and selectively deactivate selected populations of neurons in the rhesus monkey brain in an attempt to ultimately mimic more closely the neurogenetic basis of the human social behavior found in individuals with Williams syndrome.

In sum, through our James S. McDonnell Foundation Panel on Social Cognition, we have brought together a multidisciplinary team of scientists who are uniquely capable of moving between the Williams patient population and the appropriate animal model for social cognition, the rhesus monkey. This group of leading investigators is now proposing to take the exciting next steps forward in developing strategies for bridging genes to brain to cognition.




Adolphs, R., (1999). Social cognition and the human brain. Trends in Cognitive Sciences. (12), 3, 469-479.


Adolphs, R., Tranel, D., & Damasio, A. (1998). The human amygdala in social judgment. Nature, 393, 470-474.


Amaral, D.G. (2001) The primate amygdala and the neurobiology of social behavior: Implications for understanding social anxiety. Biological Psychiatry (In press).


Bachevalier J, Brickson M, Hagger C (1993) Limbic-dependent recognition memory in monkeys develops early in infancy. NeuroReport 4:77-80.


Bellugi, U.& St. George, M. (Eds.) (2000). Special Issue: Linking Cognitive Neuroscience and Molecular Genetics: New Perspectives from Williams Syndrome, Journal of Cognitive Neuroscience (1)12, pp. 1-107.


Bellugi, U., Adolphs, R., Cassady, C. & Chiles, M. (1999). Towards the neural basis for hypersociability in a genetic syndrome. NeuroReport, 10, 1653-1657.


Bellugi, U., Lichtenberger, L., Jones, W., Lai, Z., & St. George, M. (2000). The neurocognitive profile of Williams syndrome: A complex pattern of strengths and weaknesses. Journal of Cognitive Neuroscience (1) 12, pp. 7-29.


Bellugi, U., Lichtenberger, L., Mills, D., Galaburda, A. & Korenberg, J.R. (1999). Bridging cognition, brain and molecular genetics: Evidence from Williams syndrome. Trends in Neurosciences, (22) 5, 197-207.


Bellugi, U., Korenberg, J.R., & Klima, E.S (2001). Williams syndrome: An exploration of neurocognitive and genetic features. In M. Posner, Editor, Special Issue of Clinical Neurosciences Research, 1: 217-229.


Buxton, R. B. & Frank, L. R. (1997) A model for the coupling between cerebral blood flow and oxygen metabolism during neural stimulation. Journal of Cerebral Blood Flow and Metabolism, 17, 64-72.


Buxton, R. B., Frank, L. R., Wong, E. C., Siewert, B., Warach, S. and Edelman, R. R. (1998a) A general kinetic model for quantitative perfusion imaging with arterial spin labeling. Magnetic. Resonance in Medicine 40, 383-396.


Buxton, R. B., Wong, E. C. and Frank, L. R. (1998b) Dynamics of blood flow and oxygenation changes during brain activation: the balloon model. Magnetic Resonance in Medicine 39, 855-864.


Cloninger, C. R., Przybeck, T.R., Svrakic, D.M., & Wetzel, R.D., (1994). The Temperament and Character Inventory (TCI): A Guide to Its Development and Use. St. Louis, MO: Center for Psychobiology of Personality, Washington University.


Emery, N. J., Capitanio, J. P., Mason, W. A., Machado, C. J., Mendoza, S. P., & Amaral, D. G. (2001). The effects of bilateral lesions of the amygdala on dyadic social interactions in rhesus monkeys (Macaca mulatta). Behavioral Neuroscience, (115) 3, 515-544.


Francke, U. (1999). Williams-Beuren syndrome: genes and mechanisms. Human Molecular Genetics, (8) 10, 1947-54.


Franke, Y., Peoples, R. J., & Francke, U. (1999). Identification of GTF2IRD1, a putative transcription factor within the Williams-Beuren syndrome deletion at 7q11.23. Cytogenetics and Cell Genetics, 86(3-4), 296-304.


Galaburda, A., & Bellugi, U. (2000). Multi-level analysis of cortical neuroanatomy in Williams syndrome, Journal of Cognitive Neuroscience (1) 12, pp. 74-88.


Goldsmith, H., & Rothbart, M., (1992). The laboratory temperament assessment battery: Locomotor version. Unpublished test manual. Eugene, OR: Department of Psychology, Unive. Oregon.


Hoogenraad, C., Eussen, B., Langeveld, A., van Haperen, R., Winterberg, S. (1998). The murine CYLN2 gene: genomic organization, chromosome localization, and comparison to the human gene that is located within the 7q11.23 Williams syndrome critical region. Genomics, (53) 3, 348-358.


Jones, W., Anderson, D., Reilly, J., & Bellugi, U. (1998) Emotional expression in infants and children with williams syndrome: A relationship between temperament and genetics? Journal of the International Neuropsychological Society, 4, 56.


Jones, W., Bellugi, U., Lai, Z., Chiles, M., Reilly, J., Lincoln, A., & Adolphs, R. (2000). Hypersociability in Williams syndrome, Journal of Cognitive Neuroscience (1) 12, pp. 30-46.


Justice, C. M., Den, Z., Nguyen, S. V., Stoneking, M., Deininger, P. L., Batzer, M. A., & Keats, B. J. (2001). Phylogenetic analysis of the Friedreich ataxia GAA trinucleotide repeat. Journal Molecular Evolution, 52(3), 232-238.


Kagan, J., Snidman, N., & Arcus, D. (1998). Childhood derivatives of high and low reactivity in infancy. Child Development, 69(6), 1483-1493.


Kalin N.H, Shelton S.E, Davidson R.J, Kelley A.E. (2001) The primate amygdala mediates acute fear but not the behavioral and physiological components of anxious temperament. J Neurosci 21:20672074.


Korenberg, J., Chen, X-N., Hirota, H., Lai, Z., Bellugi, U., Burian, D., Roe, B., & Matsoka, R. (2000). Genome structure and cognitive map of Williams syndrome. Journal of Cognitive Neuroscience (1)12, pp. 89-107.


Korenberg, J.R., Chen, X-N., Shi, Z-Y., Schmitt, E., Bellugi, U., Reiss, A., Mills, D., Galaburda, A. (Under review, 2001). Williams Syndrome: Genes and pathways responsible for human cognition.


Korenberg, J .R., Chen, X., Sun, Z., Shi, Z., Ma, S., Vataru, E., Yimlamai, D., Weissenbach, J. S., Shizuya, H., Simon, M. I., Gerety, S. S., Nguyen, H., Zemsteva, I. S., Hui, L., Silva, J., Wu, X., Birren, B. W., and Hudson, T. J. (1999). Human Genome Anatomy: BACs Integrating the Genetic and Cytogenetic Maps of Bridging Genome and Biomedicine. Genome Research, 9(10), 994-1001.


Losh M, Bellugi U, Reilly J, & Anderson D. (2000). Narrative as a Social Engagement Tool: The Excessive Use of Evaluation in Narratives from Children with Williams Syndrome. Narrative Inquiry, 10 (2), 1-26.


Mills, D., Alvarez, T., St. George, M., Applebaum, L., Bellugi, U., & Neville, H. (2000). Electrophysiological studies of face processing in Williams syndrome. Journal of Cognitive Neuroscience (1) 12, pp. 47-64.


Peoples, R., Franke, Y., Wang, Y. K., Perez-Jurado, L., Paperna, T., Cisco, M., & Francke, U. (2000). A physical map, including a BAC/PAC clone contig, of the Williams- Beuren syndrome--deletion region at 7q11.23. American Journal of Human Genetics, 66(1), 47-68.


Perez Jurado, L. A., Wang, Y., Peoples, R., Coloma, A., Cruces, J., Francke, U. (1998). A duplicated gene in the break point regions of the 7q11.23 Williams-Beuren syndrome deletion encodes the initiator binding protein TFII-I and BAP-135, a phosphorylation target of BTK. Human Molecular Genetics 7(3), 325-334.


Raichle, M.E. (1998), Imaging the mind. Seminars in Nuclear Medicine 28(4), 278-89.


Suomi, S. J. (2000). A biobehavioral perspective on developmental psychopathology: Excessive aggression and serotonergic dysfunction in monkeys. In A. J. Sameroff, M. Lewis, & S. Miller (Eds.), Handbook of developmental psychopathology. New York: Plenum Press, pp. 237-256.


Wolf, D. P., Meng, L., Ouhibi, N., & Zelinski-Wooten, M. (1999). Nuclear transfer in the rhesus monkey: practical and basic implications. Biological Reproduction 60(2), 199-204.


Introduction Project 1 Project 2

Project 3

Project 4 Project 5 Project 6 Conclusion


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