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Content archived on 2024-04-19

Genomic studies of expanded unstable trinucleotide sequences in relation to hereditable disorders


Genome wide methods for mutational analvsis have recently developed in several genome centers. The driving force has been the observation that general methods may be very cost effective relative to traditional isolation and Cloning of single genes.
Three important inherited disorders have recently been explained at the molecular level by the finding that,expanded trinucleotide repeat sequences disrupt the normal function of a gene. Fragile-X mental retardation, myotonic dystrophy and Kennedy-disease (spino-bulbar-muscular atrophy) are thus caused by a new class of mutations. These findings imply that multiple disorders of great social and economic impact may depend on this disease mechanism. We have consequently developed a novel genome wide analysis method, RED (Repeat Expansion Detection). Using this method we have already identified some novel expanded repeats in the genome. This application is aimed at developing the RED system to rapidly elucidate the molecular mechanism behind numerous inherited disorders. To this end it is important to collect large families from multiple sites within Europe.
once trinucleotide expansion is found in correlation to a particular disease, the new method also provides the tools necessary for direct cloning approaches. Every new disease where this mechanism can be identified constitutes a breakthrough in understanding of the molecular mechanisms for the disease and also enables a rapid molecular diagnosis. Examples of diseases that we have reason to believe could be caused by repeat expansion based on the clinical phenotypeinclude: amyothrophic lateral sclerosis (ALS), Huntington's disease, manic-depressive disease and olivo-ponto cerebellar atrophy. Interestingly, as is the case with the three previously identified diseases all of the proposed disorders primarily affectthebrain and are socially and economically devastating. Clear cut benefits include the development of diagnostic tools for a number of diseases that today are hard to analyse. Furthermore, the development of a new tool to study the genome provides a unique opportunity to study the behavior of the commonly found repeat elements within the genome, on a population wide basis.


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Academisch Ziekenhuis bij de Universiteit van Amsterdam
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1105 AZ Amsterdam

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