This application presents a career development program that integrates the fields of human genetics, molecular neuroscience, and developmental-behavioral pediatrics (DBP). Dr. Gupta's career goal is to become an independent investigator who combines expertise in genetics and neurobiology to elucidate the neural systems involved in the pathophysiology of autism spectrum disorders (ASDs). A fuller picture of how ASDs develop will not only provide insights into treatment design but also advance our understanding of the biological basis of human cognition. She completed a PhD in neuroscience at the University of Pennsylvania and a clinical fellowship in DBP at the Children's Hospital of Philadelphia and Yale University School of Medicine. She obtained postdoctoral training in rare variant gene discovery in the laboratory of Matthew State, MD, PhD, a leader in the field of psychiatric genetics. She will develop expertise in molecular neuroscience under the guidance of Pietro De Camilli, MD, a pioneer in the field of synaptic biology. In addition, an advisory team of highly-regarded scientists will provide scientific and career advice. The objective of the research plan is to identify and characterize candidate genes at the neural synapse for ASDs. Dr. Gupta identified Piccolo (PCLO) as a candidate gene when it was found to be transected by a chromosomal inversion in a patient with ASD. PCLO, a major component of the presynaptic cytoskeletal matrix, has diverse functional domains and binds a wide variety of molecules. It appears to have a key role in orchestrating the sequence of events from synaptic vesicle clustering at the active zone to exocytosis and endocytosis. It is an intriguing finding given that a number of candidate genes for ASD, such as the NLGNs, NRXN1, and SHANK3, are converging at the neural synapse, indicating that the synapse is a site of damage. As the list of candidate genes grows, it has become critical to comprehensively analyze the functional consequences of patient mutations in order to start unraveling the pathophysiology of the disorder. With that purpose, this project aims to: (1) characterize the precise genetic abnormalities in the index case, (2) determine the extent of PCLO's involvement in the larger patient population through sequence and CNV analysis, (3) characterize the functional consequences of patient mutations in PCLO, and (4) identify additional synaptic genes which contribute to the disorder. The plan is to use PCLO as a starting point to trace a neural system which underlies ASD. Dr. Gupta has recruited an outstanding group of mentors and advisors to guide the design and conduct of experiments and analysis of results. They will support the candidate as she develops an independent research program. She has formulated a plan for additional didactics and intensive workshops to deepen her understanding of human genetics and synaptic biology. She will take full advantage of the resources of the Yale Child Study Center, an internationally recognized leader in the clinical evaluation and research of ASDs.

Public Health Relevance

Autism spectrum disorders (ASDs) are strongly genetic, and the neural synapse has been implicated as a site of damage in ASDs. This research aims to identify and characterize synaptic genes which are associated with the disorder. The goal is to elucidate the neural systems involved in the pathophysiology of ASDs, which will provide insights into the development of targeted treatments.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Clinical Investigator Award (CIA) (K08)
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Behavioral Genetics and Epidemiology Study Section (BGES)
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Rosemond, Erica K
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Yale University
Schools of Medicine
New Haven
United States
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Gupta, Abha R; Westphal, Alexander; Yang, Daniel Y J et al. (2017) Neurogenetic analysis of childhood disintegrative disorder. Mol Autism 8:19
Murdoch, John D; Gupta, Abha R; Sanders, Stephan J et al. (2015) No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins. PLoS Genet 11:e1004852
Griesi-Oliveira, K; Acab, A; Gupta, A R et al. (2015) Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol Psychiatry 20:1350-65
Sanders, Stephan J; Murtha, Michael T; Gupta, Abha R et al. (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237-41
Novarino, Gaia; El-Fishawy, Paul; Kayserili, Hulya et al. (2012) Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 338:394-7
Sanders, Stephan J; Ercan-Sencicek, A Gulhan; Hus, Vanessa et al. (2011) Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70:863-85