The lab uses a variety of tools (genetics, imaging, animal models) to study two important clinical domains: autism and epilepsy. We not only seek to discover the causes of these conditions but to develop new treatments. Below is a sampling of ongoing projects. If you are interested in rotating in or joining the lab, please contact Dr. Sherr by email: email@example.com.
The genetics of epilepsy: We have focused on a specific group of epilepsies, the epileptic encephalopathies (EE), that can be associated with autism and intellectual disability. We recently published a manuscript (Nature. 2013; 501(7466): 217-21. PMID: 23934111) that used exome sequencing in family trios to identify novel EE genes and to show that de novo genetic mutations are key for pathogenesis. We are using similar tools as well as animal models (including using CRISPR tools for mutagenesis) to discover new causes and to study the specific mutations found in patients.
Genetics First Approach to Autism: The 16p11.2 copy number variations (CNV; both deletion and duplication) are two of the most common genetic events associated with autistic spectrum disorder (ASD). We lead a network of scientists (SVIP; http://www.simonsvipconnect.org/) investigating the brain imaging changes (MRI, fMRI, MEG) and cognitive, and behavioral features of individuals with 16p11.2 deletions or duplications. By studying a group of individuals who all share the same genetic change, we hope to discover novel insights that explain how disrupted brain function can lead to the specific behavioral and cognitive changes associated with ASD. A recent publication (PMID: 24790192) highlights the potential of this approach.
Development of Blood-based biomarkers for autism: Advances in autism genetics and in the study of animal models provide evidence to suggest that some biochemical pathways are commonly affected in autistic patients. Our lab has shown that the activity level of specific selected intracellular signaling pathways are altered in ASD patients and that these measurements may be predictive of ASD status in presymptomatic children. Work is ongoing to elucidate the biology underlying these observations.
Gene discovery in human brain malformations: Our lab has shown that de novo and inherited genetic events play an important role in causing disorders of cerebral development, specifically focusing on patients with agenesis of the corpus callosum (ACC). ACC has a strong association with autism, as exemplified by Kim Peek, who has ACC and whose life was fictionalized in the movie, Rain Man. When novel ACC genes are identified, we develop animal models to investigate the implications on cerebral development. (See: PMID: 24098143 and PMID: 23453666).
Owen JP, Chang YS, Pojman NJ, Bukshpun P, Wakahiro ML, Marco EJ, et al. Aberrant white matter microstructure in children with 16p11.2 deletions. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2014;34(18):6214-23. doi: 10.1523/JNEUROSCI.4495-13.2014. PubMed PMID: 24790192.
Edwards TJ, Sherr EH, Barkovich AJ, Richards LJ. Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes. Brain: a journal of neurology. 2014. doi: 10.1093/brain/awt358. PubMed PMID: 24477430.
Sherr EH, Michelson DJ, Shevell MI, Moeschler JB, Gropman AL, Ashwal S. Neurodevelopmental disorders and genetic testing: Current approaches and future advances. Annals of neurology. 2013. doi: 10.1002/ana.23950. PubMed PMID: 23775934.
Sajan SA, Fernandez L, Nieh SE, Rider E, Bukshpun P, Wakahiro M, et al. Both rare and de novo copy number variants are prevalent in agenesis of the corpus callosum but not in cerebellar hypoplasia or polymicrogyria. PLoS genetics. 2013;9(10):e1003823. doi: 10.1371/journal.pgen.1003823. PubMed PMID: 24098143; PubMed Central PMCID: PMC3789824.
Owen JP, Li YO, Ziv E, Strominger Z, Gold J, Bukhpun P, et al. The structural connectome of the human brain in agenesis of the corpus callosum. NeuroImage. 2013;70:340-55. doi: 10.1016/j.neuroimage.2012.12.031. PubMed PMID: 23268782.
Owen JP, Li YO, Yang FG, Shetty C, Bukshpun P, Vora S, et al. Resting-state networks and the functional connectome of the human brain in agenesis of the corpus callosum. Brain connectivity. 2013;3(6):547-62. doi: 10.1089/brain.2013.0175. PubMed PMID: 24063289; PubMed Central PMCID: PMC3868398.
Lau YC, Hinkley LB, Bukshpun P, Strominger ZA, Wakahiro ML, Baron-Cohen S, et al. Autism traits in individuals with agenesis of the corpus callosum. Journal of autism and developmental disorders. 2013;43(5):1106-18. doi: 10.1007/s10803-012-1653-2. PubMed PMID: 23054201; PubMed Central PMCID: PMC3625480.
Jones-Davis DM, Yang M, Rider E, Osbun NC, da Gente GJ, Li J, et al. Quantitative trait loci for interhemispheric commissure development and social behaviors in the BTBR T(+) tf/J mouse model of autism. PloS one. 2013;8(4):e61829. Epub 2013/04/25. doi: 10.1371/journal.pone.0061829. PubMed PMID: 23613947; PubMed Central PMCID: PMCPMC3626795.
Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501(7466):217-21. Epub 2013/08/13. doi: 10.1038/nature12439. PubMed PMID: 23934111; PubMed Central PMCID: PMCPMC3773011.
Akizu N, Shembesh NM, Ben-Omran T, Bastaki L, Al-Tawari A, Zaki MS, et al. Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia. American journal of human genetics. 2013;92(3):392-400. doi: 10.1016/j.ajhg.2013.02.004. PubMed PMID: 23453666; PubMed Central PMCID: PMC3591854.
Zufferey F, Sherr EH, Beckmann ND, Hanson E, Maillard AM, Hippolyte L, et al. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. Journal of medical genetics. 2012;49(10):660-8. Epub 2012/10/12. doi: 10.1136/jmedgenet-2012-101203. PubMed PMID: 23054248; PubMed Central PMCID: PMC3494011.
Marco EJ, Abidi FE, Bristow J, Dean WB, Cotter P, Jeremy RJ, et al. ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal. Journal of medical genetics. 2008;45(2):100-5. Epub 2007/09/26. doi: 10.1136/jmg.2007.052324. PubMed PMID: 17893116.