Building protein interaction maps for Down's syndrome

Briefings in Functional Genomics, Aug 2004

Now that the complete sequences for human chromosome 21 and the orthologous mouse genomic regions are known, reasonably complete, conserved, protein-coding gene catalogues are also available. The central issue now facing Down's syndrome researchers is the correlation of increased expression of specific, normal, chromosome 21 genes with the development of specific deficits in learning and memory. Because of the number of candidate genes involved, the number of alternative splice variants of individual genes and the number of pathways in which these genes function, a pathway analysis approach will be critical to success. Here, three examples, both gene specific and pathway related, that would benefit from pathway analysis are discussed: (1) the potential roles of eight chromosome 21 proteins in RNA processing pathways; (2) the chromosome 21 protein intersectin 1 and its domain composition, alternative splicing, protein interactions and functions; and (3) the interactions of ten chromosome 21 proteins with components of the mitogen-activated protein kinase and the calcineurin signalling pathways. A productive approach to developing gene-phenotype correlations in Down's syndrome will make use of known and predicted functions and interactions of chromosome 21 genes to predict pathways that may be perturbed by their increased levels of expression. Investigations may then be targeted in animal models to specific interactions, intermediate steps or end-points of such pathways and the downstream—perhaps amplified—consequences of gene dosage directly assessed. Once pathway perturbations have been identified, the potential for rational design of therapeutics becomes practical.

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Building protein interaction maps for Down's syndrome

Building protein interaction maps for Down's syndrome Katheleen Gardiner 0 1 2 Muriel T. Davisson 0 1 2 Linda S. Crnic Date received (in revised form): 0 1 2 th May 0 1 2 0 Linda S. Crnic is the Director of the Colorado Mental Retardation and Developmental Disabilities Research Center and a professor of pediatrics and psychiatry at the University of Colorado Health Sciences Center 1 Muriel T. Davisson is a senior staff scientist and Director of Genetic Resources at The Jackson Laboratory in Bar Harbor , Maine 2 Katheleen Gardiner is a professor in the Eleanor Roosevelt Institute at the University of Denver and an adjoint associate professor of biochemistry and molecular genetics at the University of Colorado Health Sciences Center Now that the complete sequences for human chromosome 21 and the orthologous mouse genomic regions are known, reasonably complete, conserved, protein-coding gene catalogues are also available. The central issue now facing Down's syndrome researchers is the correlation of increased expression of specific, normal, chromosome 21 genes with the development of specific deficits in learning and memory. Because of the number of candidate genes involved, the number of alternative splice variants of individual genes and the number of pathways in which these genes function, a pathway analysis approach will be critical to success. Here, three examples, both gene specific and pathway related, that would benefit from pathway analysis are discussed: (1) the potential roles of eight chromosome 21 proteins in RNA processing pathways; (2) the chromosome 21 protein intersectin 1 and its domain composition, alternative splicing, protein interactions and functions; and (3) the interactions of ten chromosome 21 proteins with components of the mitogen-activated protein kinase and the calcineurin signalling pathways. A productive approach to developing gene-phenotype correlations in Down's syndrome will make use of known and predicted functions and interactions of chromosome 21 genes to predict pathways that may be perturbed by their increased levels of expression. Investigations may then be targeted in animal models to specific interactions, intermediate steps or end-points of such pathways and the downstream - perhaps amplified - consequences of gene dosage directly assessed. Once pathway perturbations have been identified, the potential for rational design of therapeutics becomes practical. trisomy 21; cognitive deficits; pathway perturbation; MAP kinase; calcineurin; intersectin; RNA processing - INTRODUCTION With an incidence of approximately one in 700 live births, Down’s syndrome (DS) is the most common genetic cause of mental retardation.1 DS, or trisomy 21, is caused by an extra, third, copy of all or part of human chromosome 21 and the consequent overexpression of genes encoded within it. The complete phenotype of DS is complex and variable in severity; most organs and organ systems are involved, resulting in heart defects, immune system deficiencies, hypotonia, skeletal abnormalities and an increased risk of leukaemia.2 The mental retardation, manifested in specific cognitive and behavioural deficits, is the primary deficit common to all persons with DS and, thus, may be the most critical issue for quality of life for the general DS population. The average IQ is 50 and ranges from severely retarded to low normal.3 This does not reflect a generalised dysfunction, but rather involves impairment of specific learning and memory tasks requiring specific regions of the brain. For example, children aged 18 – 30 months with DS were successful in the learning phase of three hippocampal-specific tasks, but, in the memory phase, they were successful in only two of the three tasks.4 Pennington et al.5 studied older children with DS and specific dysfunction was demonstrated in: (1) hippocampal tasks that did not involve the parahippocampal or the pirihinal region and (2) in prefrontal cortex tasks, affecting verbal but not non-verbal tasks. Specific neuroanatomical features of the DS brain include decreased sizes of the hippocampus, pre-frontal cortex and Challenges in DS include the large number of candidate genes and the modest increases in their expression levels cerebellum, a decrease in dendritic arborisation, premature degeneration of functional markers in the cholinergic neurones of the basal forebrain and development of plaques and tangles characteristic of Alzheimer’s disease.4,6 Together, these observations show the specificities in DS-associated neuroabnormalities. The challenge now is to link specific genes and the pathways in which they function to these features. MOLECULAR HYPOTHESIS The rational basic assumptions guiding DS research are that: (1) individual chromosome 21 genes will show gene dosage effects that increase expression by 50 per cent at the RNA and the protein levels; (2) at least some of these increases will result in perturbations of the pathways and cellular processes in (...truncated)


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Katheleen Gardiner, Muriel T. Davisson, Linda S. Crnic. Building protein interaction maps for Down's syndrome, Briefings in Functional Genomics, 2004, pp. 142-156, 3/2, DOI: 10.1093/bfgp/3.2.142