 |
University of California, San Francisco |  |
About UCSF | |
Search UCSF | |
UCSF Medical Center |
|
 |
|
||||||||||||||||||||||||||
|
||||||||||||||||||||||||||
|
|
 Institute for Human Genetics Autism is a clinical syndrome with a diversity of clinical manifestations and causes, many of which are likely to be genetic. The syndrome is now often referred to as the “Autisms” to accurately reflect this heterogeneity. One important hypothesis that may explain the causes of the autisms is a deficit in long-range connectivity, both functional and anatomic. One principal example of this is patients with agenesis of the corpus callosum (AgCC). Many patients with AgCC have ADI/ADOS defined autism or clinical symptoms within the autistic spectrum, as exemplified by Kim Peek, whose life was fictionalized in the movie, Rain Man. The first meeting of the Autism Consortium took place on February 11, 2008. Members are listed below. Lisa Croen Ph.D. Dr. Croen joined the Division of Research as a perinatal epidemiologist in 2000. Her research interests include the epidemiology of autism and other neurodevelopmental disorders, environmental exposures and gene/environment interaction, and adverse perinatal outcomes. Currently she is a Principal Investigator on two large federally funded autism studies. The first is the Study to Explore Early Development, a large, national case-control study focused on environmental and genetic risks for autism, funded by the Centers for Disease Control and Prevention. The second is the Early Markers for Autism (EMA) Study, an investigation of prenatal and neonatal biologic markers for autism, funded by the National Institutes of Health. She is also Co-Investigator on the California Autism Twins Study (CATS), funded by the National Institute of Mental Health. Karl Deisseroth, M.D., Ph.D. Ricardo Dolmetsch, Ph.D. Dr. Dolmetsch's laboratory studies the biological basis of autism spectrum disorders. His laboratory is using a combination of genetics and novel stem cell technologies to investigate the development of neurons in children with autism. Dr. Dolmetsch and his colleagues have developed novel assays to study neuronal development in culture and are using these to identify defects in neurons from patients. Dr. Dolmetsch's laboratory is also generating mouse models of autism by introducing specific mutations associated with autism into mice. Finally they are using fly genetics to study the signaling cascades that lead to autism. Carl Feinstein, M.D. Autism and Asperger's Disorder. Genetically-based neurodevelopmental disorder, including Velocardiofacial Syndrome, Smith-Magenis Syndrome, Williams Syndrome, and Fragile X Syndrome. Intellectual Disability (mental retardation) and psychiatric disorders. Developmental Language Disorder and Learning Disabilities. Sensory impairment in children, including visual and hearing impairment. Psychiatric aspects of medical illness and disability in children. Jane Gitschier, Ph.D. Dr. Gitschier's laboratory’s curiosity about the genesis of autism is an outgrowth of their findings from two different lines of research. First, through their study of several inherited disorders of heavy metal metabolism, they have come to appreciate that, theoretically, some children might harbor a genetic sensitivity to heavy metals, and that such sensitivity, in conjunction with environmental exposure, particularly in either vaccines or the food supply, might manifest in impaired neurodevelopment. To begin to dissect the pathway for mercury metabolism in mammals, Dr. Gitschier's lab have assayed different inbred strains of mice for sensitivity to ethylmercury and are currently attempting to map genetic loci that are responsible for these differences. Second, in a study on the genetic basis of absolute pitch perception, also known as perfect pitch, some subjects have reported autism spectrum disorder either in themselves or in their relatives. As absolute pitch is a savant-like ability, and as such traits are known to accompany autism, They anticipate that discovery of the genetic elements that underlie absolute pitch perception may provide some clues into the molecular underpinnings of autism. Judith Grether, Ph.D. As a perinatal epidemiologist, Dr. Grtether's research interests focus on surveillance of autism and other developmental disabilities, etiologic studies of prenatal and early childhood factors that may contribute to autism and related disorders, and studies of early biologic markers that may identify newborns at high risk. Joachim Hallmayer, M.D. Dr. Hallmayer's main focus of research is to find genetic markers linked to autism and pervasive developmental disorders. A second research focus is to resolve the heterogeneity of clinical phenotypes such as schizophrenia into genetically simpler, quantifiable components, thus facilitating the search for susceptibility genes for these disorders. Several phenotypes that have been reported to correlate with clinical schizophrenia are currently being studied. These include neurocognitive variables such as sustained attention and a number of event-related potentials such as mismatch negativity. Steve Hamilton, M.D., Ph.D. Dr. Hamilton’s laboratory is approaching autism genetics by investigating sequence variation in genes linked to neuronal development and differentiation. The primary focus is on the identification of rare but penetrant alleles in transcription factor and signal transduction genes that may illuminate functional analyses in collaboration with basic neuroscientists (John Rubenstein, Ben Cheyette). Antonio Hardan, M.D. Dr. Hardan is the director of the Autism and Developmental Disorders Clinic at Packard Children's Hospital. He has more than 15 years experience in working with individuals with autism. He is an expert in providing psychopharmacological treatment to these individuals. His research work has focused on investigating the neurobiology of autism using neuroimaging techniques and the development of innovative treatment strategies for this disorder. He has published extensively in this field. Lily Jan, Ph.D. Yuh Nung Jan, Ph.D. Susan McConnell, Ph.D. Susan McConnell is the Susan B. Ford Professor in the Department of Biological Sciences at Stanford University. She joined the Stanford faculty in 1989. McConnell studies the development of the cerebral cortex, the brain region that controls our highest cognitive and perceptual functions. The nerve cells of the cortex are generated during fetal life; once these cells are born, they migrate over long distances before forming connections with other nerve cells. McConnell explores the mechanisms by which young neurons acquire an identity and establish specific connections. Her studies provide insights into the process of how the brain wires itself up during normal development. Although McConnell does not work directly on autism, she has served on the Scientific Advisory Committees of Cure Autism Now and the NIH STAART and CPEA Autism Centers. Vinod Menon, Ph.D. Dr. Menon's lab is interested in studying (1) the organization and development of large-scale brain networks in autism and (2) the cognitive neuroscience of mathematical reasoning skills in children and adults with autism. Karen J. Parker, Ph.D. Len A. Pennacchio, Ph.D. Dr. Pennacchio heads JGI's Genetic Analysis Program and the Genomic Technologies Program. Dr. Pennacchio was raised in the North Bay and earned his Bachelor’s degree in biology from Sonoma State University. He received his Ph.D. in 1998 from the Department of Genetics at Stanford University. During his graduate studies, he worked with Richard Myers to uncover the genetic cause of a rare form of human epilepsy and subsequently generated one of the first mouse models for epilepsy. In 1999, he joined Edward Rubin's laboratory as an Alexander Hollaender Distinguished Fellow at Lawrence Berkeley National Laboratory where he identified a novel apolipoprotein involved in human and mouse triglyceride metabolism. In 2003, he became the Head of the Genetic Analysis Program at the DOE Joint Genome Institute and a Staff Scientist at Lawrence Berkeley National Laboratory. In 2007, he took charge of the Genomic Technologies Program. Dr. Pennacchio is a recipient of the Presidential Early Career Award for Scientists and Engineers. His research is focused on understanding how DNA sequence variation contributes to human phenotypes and disease, including autism. Major efforts are focused on exploiting next generation DNA sequencing to link genes to traits at an unprecedented scale and cost-effectiveness. Neil Risch, Ph.D. John Rubenstein, M.D., Ph.D. Dr. Rubenstein's laboratory is interested in studying the genes that regulate regional specification and differentiation of the mammalian forebrain. In addition, they have a long-standing interest in integrating these findings to better understand the development and evolution of forebrain neural systems and to help elucidate mechanisms underlying human neurodevelopmental disorders such as Autism. Dr. Rubenstien's laboratory has several types of projects: Transcription factors that control regional specification of brain subdivisions: Ongoing studies focus on defining the transcription factors that control CNS development. These include the roles of the Nkx genes in specifying ventral neural progenitors (e.g., Nkx2.1 for globus pallidus principal neurons and cortical interneurons). These results are contributing towards elucidating the transcription factor code that defines the development programs of forebrain progenitor zones. This information shows linkage of regional and cell-type specification in the telencephalon; i.e., distinct telencephalic progenitor zones generally produce neurons that utilize different types of neurotransmitters. Ventral regions produce cholinergic, intermediate regions produce GABAergic and dorsal regions produce glutamatergic neurons. Dlx Transcription factors that control craniofacial patterning: Often neuropsychiatric disorders are associated with craniofacial dysmorphologies. Studies of Dlx function in craniofacial neural crest have illuminated the role of these genes in patterning the jaw and middle ear skeleton, findings that have important evolutionary and medical ramifications. Cortical inhibitory neurons are generated in the basal ganglia and tangentially migrate to the cortex: There is migration of GABAergic neurons from the subcortical telencephalon into the cerebral cortex, where these cells become the major class of inhibitory neurons in the mouse. There is a similar tangential migration for cholinergic striatal interneurons. Dr. Rubenstein and his colleagues are currently defining the molecular mechanisms that control the movement and integration of the migratory cells to their destinations. Control of mature GABAergic cortical interneuron function: Mutation of Dlx1 leads to an age-dependent death of a subset of dendrite innervating cortical interneurons. As these interneurons die, the mutant mice develop epilepsy. Dr. Rubenstien's lab is currently learning how Dlx function in neurons controls their function and survival. These insights could be pertinent for neuropsychiatric disorders, such as autism and schizophrenia, in which patients show largely normal development prior to the onset of symptoms. With Arturo Alvarez-Buylla, Scott Baraban and Arnold Kriegstein, they are developing methods for interneuron transplantation to treat forebrain disorders, such as epilepsies. Elliott Sherr, M.D., Ph.D. Dr. Sherr and his lab members use a multi-faceted approach to study the genetics and biology of AgCC and use this as a platform to understand autistic behaviors and brain development in the broader autism patient population. AgCC and Human Genetics: Dr. Sherr has assembled a cohort of over 400 individuals with callosal abnormalities, for whom he has comprehensive radiologic and clinical information. He is approaching gene discovery from multiple perspectives: 1. De novo copy number variation. Dr. Sherr and his lab members have previously shown that de novo chromosomal deletions and duplications may play an important role in AgCC. They are now screening their full cohort using Illumina SNP arrays looking for these de novo CNVs and other de novo changes such as uniparental disomy, with this highly detailed platform. Once regions are identified, they are carefully examining the candidate genes in these regions to look for smaller mutations in candidate genes from patients who did not harbor de novo CNV. 2. Recessive disorders. Dr. Sherr's laboratory is actively pursuing homozygosity mapping from consanguineous pedigrees in patients with AgCC. Because of their detailed imaging analysis for each patient, they have been able to identify novel syndromes for which AgCC and autism are shared with other brain development changes. Dr. Sherr has implemented a new approach, exon capture coupled with high throughput sequencing to streamline the process from patient ascertainment to gene discovery. Characterization of long-range connectivity in AgCC cohort: While the absence of the corpus callosum is what triggers the enrollment in Dr. Sherr's study, it is not this anatomic finding alone that accounts for the autistic features in these patients. Dr. Sherr and his colleagues have used a novel technique, diffusion tensor imaging, to investigate how the major axon bundles of the cortex are connected in AgCC patients. They have found that the cingulum bundle, (which connects the parahippocampal gyrus to the cingulated cortex and then to the prefrontal cortex) is diminished in these AgCC patients. As these patients show deficits in executive function and working memory on standardized cognitive tests, these anatomic changes may be the cause. Patients with autism and schizophrenia also show similar behavioral and anatomic changes. This highlights what Dr. Sherr and his colleagues feel to be an important connection. Many of his AgCC patients (a finding also supported in the literature) have autism, Aspergers or other symptoms in the autistic spectrum. Indeed, this connection is so robust, that Dr. Sherr and his colleagues see parallels of it in animal models (see below). AgCC and Autism in Animal Models: Dr. Sherr's goal is to understand human pathophysiology and treat patients, however, animal models often provide opportunities to better and more directly explore the full complexity of genetics and anatomy. Dr. Sherr has been investigating the mouse strain, BTBR T+tf/J (BTBR), that has both AgCC and behaviors that have face validity to autism. BTBR mice display multiple social deficits as juveniles and adults, unusual vocalizations as infants and high levels of repetitive behaviors, representing the first, second and third diagnostic symptoms of autism, respectively. These mice also have cerebral wiring deficits, most obviously being AgCC. Dr. Sherr and his colleagues are investigating the hypothesis that AgCC and other disruptions of cerebral connectivity and development in BTBR mice are intimately related to the observed autistic symptomatology. They have identified two loci that are the major contributors to the lack of the corpus callosum and are working aggressively to identify the causative genes. In collaboration with Jacki Crawley at the NIH and Ralph Adolphs at Caltech, they are investigating the interaction between the autistic behavior and genetics and also using advanced imaging and detailed histological analyses to begin to bridge the brain/behavior/gene interface. Donna Spiker, Ph.D. Dr. Spiker is Program Manager of SRI International’s Early Childhood Program. At SRI, she conducts research and evaluations about the effects of early intervention and early childhood programs and services on the development and school readiness of children ages 0-5 years, with special attention to young children with disabilities, including autism, or other special needs or risk conditions. particularly with large, national, multisite projects using experimental designs. She currently is associate director of the national Early Childhood Outcomes (ECO) Center, an Office of Special Education Programs, U.S. Department of Education project designed to develop child and family outcome measurement systems for children with disabilities from ages 0 to 5 in all states and for the federal government. Dr. Spiker also was co-principal investigator of the National Early Intervention Longitudinal Study (NEILS) at SRI from 2003-2007, a longitudinal study of a nationally representative sample of more than 3,000 children with disabilities and their families who received early intervention services (birth to age 3) and were followed until kindergarten. Under a grant from the Institute of Education Sciences, she currently is conducting data analysis of the kindergarten outcomes of the NEILS participants. Jeffrey Wall, Ph.D. Dr. Wall received his Ph.D. in Evolutionary Biology from the University of Chicago and trained as a postdoc both there and at Harvard University. Before joining the faculty at UCSF in 2007, he spent three years as a faculty member in the Department of Molecular and Computational Biology at USC. His research spans a wide range of topics in evolutionary and human genetics, including models of speciation, inference of population history from sequence polymorphism data, and analyses of whole genome association study data in admixed populations. Ching H. Wang, M.D., Ph.D. Dr. Wang’s research focuses on the molecular genetics of childhood neuromuscular and neurodevelopmental disorders. He uses cellular and animal models to study motor neuron diseases and autism. As part of his clinical practice, he makes diagnosis and provides intervention strategies for children with autism spectrum disorders in his Neurobehavior Clinic. Dr. Wang received his M.D. and his Ph.D. in Neuroscience from Northwestern University. He completed a fellowship in pediatric neurology at Columbia Presbyterian Medical Center in New York and conducted postdoctoral research on human molecular genetics at Columbia University. Dr. Wang serves as the director of the Pediatric Neuromuscular Clinic and Neurobehavior Clinic at Packard Children’s Hospital. Lauren Weiss, Ph.D. At UCSF, Dr. Weiss directs a research laboratory that investigates the genetic mechanisms controlling neuropsychiatric disorders, such as autism spectrum disorders. Her long-term goal is the genetic and molecular dissection of the social and communication deficits underlying autism in order to improve understanding, prediction, and treatment. Anthony Wynshaw-Boris, M.D., Ph.D. Autism is a devastating disorder first appearing in early childhood in which children display deficits in social behavior and language. The causes are unknown, but based on heritability estimates there is likely to be an important genetic component. Recently, children with autism were found to display increased head circumferences and potentially enlarged brains, but these phenotypes have been difficult to study. As part of an Autism Center of Excellence at UCSD, led by Eric Courchesne, children will be identified who are at risk for autism as early as one year of age. Structural and functional studies of the brains of these children will be performed at one, two and three years of age, when the diagnosis of autism can be confirmed. The imaging studies of the brains of children diagnosed with autism will be compared with controls for evidence of general and regional brain overgrowth. Variations and mutations in genes with expected roles in mitosis, neurogenesis, growth and apoptosis will be determined and correlated with autism and brain overgrowth.
|
||||||||||||||||||||||||
|
|
