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
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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)