RETT SYNDROME: GENETICS, PATHOPHYSIOLOGY, AND BIOMARKERS Release Date: January 18, 2000 NOTICE: HD-00-001 National Institute of Child Health and Human Development National Institute of Neurological Disorders and Stroke PURPOSE The National Institute of Child Health and Human Development (NICHD) and the National Institute of Neurological Disorders and Stroke (NINDS) announce an expansion of Program Announcement PAS-99-037, Rett Syndrome: Genetics, Pathophysiology, and Biomarkers, originally published in January 1999. The original announcement indicated that NICHD would support the Research Project Grant (R01) and Small Grant (R03), and NINDS would support the R01 and Exploratory/Developmental Grant (R21) mechanisms. Effective immediately, the NICHD also will support the R21 mechanism, in addition to the R01 and R03 as originally announced. This Notice also provides updated information about the NICHD Small Grants Program and Modular Grant application procedures. This Notice does not affect any other aspects of the original program announcement. PAS-99-037 should be read for application instructions and other relevant information. The addition of the R21 mechanism is intended to maximize opportunities for investigators to propose new research projects that build upon a recent discovery in Rett syndrome. Despite intense research efforts, little progress has been made until recently in understanding the cause of this disorder and in developing approaches for treatment. Although the vast majority of cases appear to be sporadic, current data suggest a genetic basis, possibly associated with the X chromosome. One such gene has now been identified, a gene that encodes a protein that binds to methylated cytosine in DNA. This protein participates with a group of proteins that link together to silence such methylated genes. Mutations in such genes result in accumulation of otherwise beneficial proteins, affecting nervous system development and maturation in a progressive and devastating way. Males whose X chromosome contains this mutated gene have no protection from these deleterious effects and die before birth. Because girls and women with Rett syndrome have two X chromosomes, and only one X chromosome is active in any given cell, some of their brain cells express normal amounts of the proteins, while others express excessive amounts. Thus, the accumulation of such proteins is slowed, but progressive, so symptoms appear by the second year of life. This revelation now provides a genetic marker for some individuals with Rett syndrome, so that the diagnosis can be made on other than clinical criteria. This discovery provides a basis for further genetic and neuropathologic studies of the pathogenesis of the effects of gene overexpression, and enables the use of recently developed animal models such as transgenic mice. The Mental Retardation and Developmental Disabilities (MRDD) Branch of the NICHD and the Neurodevelopment Section of the NINDS encourage grant applications using the R01, R03 (NICHD only), and R21 funding mechanisms to conduct studies of how to manipulate such genes to slow, reverse, or even prevent the progression of Rett syndrome. Such applications might focus on, for example: o In vivo and in vitro studies of tissues, cells, and DNA isolated from affected individuals and animal models to explore the genetic mechanisms of gene expression patterns and possible modulations to understand mechanisms of progressive nervous system dysfunction. o Development of animal models of Rett syndrome and subsequent structural and functional studies of these animal model systems to define the molecular, cellular, biochemical, and behavioral manifestations. o Hypothesis-based therapeutic strategies for managing the devastating effects of the aberrant environment that results from the accumulation of proteins in the nervous systems of Rett syndrome individuals. APPLICATION PROCEDURES The following information is supplemental to that provided in PAS-99-037: Since publication of PAS-99-037, a new announcement of the NICHD Small Grants (R03) Program has been published. Please refer to the program announcement PAR-99-126, published in the NIH Guide for Grants and Contracts on July 13, 1999, available at, for information and application instructions regarding the NICHD R03. It should be noted that all R03 and R21 applications, and all R01 applications requesting up to $250,000 direct costs per year, must be submitted in accordance with Modular Grant application procedures. Complete and detailed instructions and information on Modular Grant applications can be found at INQUIRIES Inquiries regarding this Notice should be directed to: Mary Lou Oster-Granite, Ph.D. Mental Retardation and Developmental Disabilities Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B09D, MSC 7510 Bethesda, MD 20892-7510 Telephone: 301-496-1383 FAX: 301-496-3791 E-Mail: Giovanna Spinella, M.D. Neurodevelopment Section National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2132 Rockville, MD 20892-9527 Telephone: 301-496-5821 FAX: 301-402-1501 E-Mail:

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