Release Date:  January 18, 2000

NOTICE:  HD-00-001

National Institute of Child Health and Human Development
National Institute of Neurological Disorders and Stroke


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 

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. 


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 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

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

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