Understanding the molecular biological underpinnings of human behavior and cognition is a challenge to modern biomedicine for which Williams syndrome (WMS) provides a compelling model. We have characterized the genetic structure of WMS subjects to show the two common deletions are clustered, with one centromeric and two telomeric breakpoints and that the deleted region is flanked by complex unstable duplications that vary through primate evolution and are related to the instability in humans. By combing genetic with neurocognitive, neuroanatomic and neurophysiological measures in WMS with small deletions, the results parsed the genetic origins of WMS phenotypes, suggesting the following working hypotheses: that the deletion of two genes for transcription factors, GTF2I and GTF2IRD1 was linked to aspects of defective visual- spatial cognition including global processing, to aberrant neuroanatomy of the parieto-occipital region and the cerebellum, and to event related potential (ERP) measures of face processing; further, that this pathway was separated from that underlying the WMS larger superior temporal gyrus and correlational abnormal electrophysiological measures of language, both of which were associated with other regions. Combining these electrophysiological measures of language, both of which were associated with other regions. Combining these with other data supports a unifying hypothesis, that relates decreased expression of GTF2I/GTF2IRD1 to the differential impairment of the dorsal versus the ventral visual streams and related neural pathways, perhaps through the aberrant neuroanatomy observed. The experiments proposed are designed to test these hypotheses and to generate and test new working models relating the under-expression of specific genes deleted in WMS to specific neurocognitive features. 1. The clinical and molecular structures of 250 WMS subjects will be established and combined with the neurocognitive, ERP and neuroanatomic (MRI and fMRI) results from subprojects 0001, 0002, 0003. Analyses of subjects with the common and larger deletions as well as of eight rare subjects with small deletions, will be used to define, assign and test WMS neurocognitive phenotypes versus subsets of genes in the deleted region. 4. The expression of candidate genes GTF2I and GTFIRD1 will be evaluated during human brain morphogenesis and by the generation of knock-out mouse models. The results will help to elucidate the pathways that link genes with cognitive phenotypes and to formulate approaches for testing them.
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