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A global comparison of gene expression in fetal brains from Down Syndrome and normals to assess developmental differences

Applicant Antonarakis Stylianos
Number 52845
Funding scheme NRP 38 Diseases of the Nervous System
Research institution Lab. de Diagnostique moléculaire Service de génétique médicale Dépt Gynécologie et obstétrique
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.08.1998 - 30.09.2000
Approved amount 374'800.00
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Keywords (7)


Lay Summary (English)

Lay summary
Background: Down syndrome (DS), caused by an extra copy of human chromosome 21 (tri-somy 21 or T21), is the most common genetic cause of mental retardation (~1/700 live births). Changes in the neuropathology, neurochemistry, neurophysiology, and neuropharmacology of DS patient brains indicate that there is probably abnormal development and maintenance of CNS structure and function. In addition to the mental retardation and facial characteristics, there are many other phenotypes, including congenital heart disease, early onset Alzheimer's disease and an increased risk of leukemia. Hypothesis: Of the 600-1000 genes on human chromosome 21 (HC21), the presence of an extra copy of only some of these genes in T21 may result in DS phenotypes through processes that directly or indirectly effect the expression of other genes or gene products. This may be particularly true for transcription factors or signal transducing proteins, several of which map to HC21. Thus the altered expression of genes other than those on HC21 may be responsible for some DS phenotypes.

Proposal and Aims: The goal of this study is to analyze the global gene expression between normal and T21 human fetal brains from 18-20 week embryos and detect differences that can be linked to abnormal neuronal development and thus the mental retardation of DS. The recently developed method of Serial Analysis of Gene Expression (SAGE) will be employed. Transcripts with significantly altered expression levels will be pursued for further functional studies, starting with full-length cDNA cloning and analyses of expression patterns, principally in the brain by in situ hybridization. Some of these molecular differences may be targets for therapeutic intervention.

Significance: This project will provide the first overall clear picture of many of the differences in gene expression in an aneuploid Vs normal fetal brain during CNS development. This may lead to the discovery of genes responsible for several phenotypes, principally mental retardation. The data generated from normal brains will serve as a database for the scientific community regarding gene expression profiles in human fetal brain. Progress: SAGE libraries have been prepared and are undergoing characterization prior to large scale sequencing.

Direct link to Lay Summary Last update: 21.02.2013

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