This program consists of an administrative and scientific core serving four investigative areas: (1) Biochemical Regulation; (2) Biochemistry of Neurotransmitter Receptors; (3) Neurochemical Studies in Canine Narcolepsy and (4) Clinical Neurochemical and Genetic Studies in infantile autism. The central theme of the program is that pervasive developmental disorders in children reflect central nervous system dysfunction with defined biochemical and metabolic consequences. The investigative scope of the program ranges from basic work in gene regulation, protein structure and neuropharmacology to diagnostic and therapeutic strategies in infantile autism. Each component of the program interdigitate with the other project areas while retaining a separate base of scientific inquiry. The biochemical Regulation section focuses on the regulation of the catecholamine biosynthetic enzymes, dopamine s-hydroxylase and phenylethanolamine N-methyltransferase, from genomic through posttranslational events. Studies on the structure, subunit composition and amino acid sequence of these enzymes are ongoing as is work cloning cDNA probes encoding their structure. These probes and specific antibodies will be used to investigate molecular events underlying enzyme regulation. The Receptor section studies the molecular characteristics of 5HTIb and 5HTIc receptors, is solubilizing and puriFying these proteins and developing molecular probes to study their regulation. Developmental studies examining the brain serotonergic- noradrenergic system will be a coordinated effort of the Regulation and Receptor sections. The Narcolepsy section studies neurochemical deficits in the cholinergic, dopaminergic and noradrenergic systems implicated in canine narcolepsy, a genetic disorder also occurring in children. Work on the receptors and enzymes involved in these systems is underway, as are intergroup efforts studying their ontogeny and genetic regulation. The Clinical section has accumulated a large database of children with autism and related pervasive developmental disorders, and has developed methods of subtyping them into four, more distinct, homogeneous clinical groups. Work is underway to define discrete genetic, prenatal and biochemical markers associated with these subtypes. Finally, a new project area will investigate genetic linkage in multiplex families with autistic probands, using a series of cDNA probes to identify restriction fragment polymorphisms.
| Sampath, Srirangan; Bhat, Shambu; Gupta, Simone et al. (2013) Defining the contribution of CNTNAP2 to autism susceptibility. PLoS One 8:e77906 |
| Tsang, Kathryn M; Croen, Lisa A; Torres, Anthony R et al. (2013) A genome-wide survey of transgenerational genetic effects in autism. PLoS One 8:e76978 |
| Fradin, Delphine; Cheslack-Postava, Keely; Ladd-Acosta, Christine et al. (2010) Parent-of-origin effects in autism identified through genome-wide linkage analysis of 16,000 SNPs. PLoS One 5: |
| Weiss, Lauren A; Arking, Dan E; Gene Discovery Project of Johns Hopkins & the Autism Consortium et al. (2009) A genome-wide linkage and association scan reveals novel loci for autism. Nature 461:802-8 |
| Arking, Dan E; Cutler, David J; Brune, Camille W et al. (2008) A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 82:160-4 |
| Benayed, Rym; Gharani, Neda; Rossman, Ian et al. (2005) Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus. Am J Hum Genet 77:851-68 |
| Spiker, Donna; Lotspeich, Linda J; Dimiceli, Sue et al. (2002) Behavioral phenotypic variation in autism multiplex families: evidence for a continuous severity gradient. Am J Med Genet 114:129-36 |
| Spiker, D; Lotspeich, L J; Dimiceli, S et al. (2001) Birth order effects on nonverbal IQ scores in autism multiplex families. J Autism Dev Disord 31:449-60 |
| Salmon, B; Hallmayer, J; Rogers, T et al. (1999) Absence of linkage and linkage disequilibrium to chromosome 15q11-q13 markers in 139 multiplex families with autism. Am J Med Genet 88:551-6 |
| Risch, N; Spiker, D; Lotspeich, L et al. (1999) A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 65:493-507 |
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