In a study published today in the online version of PLoS Genetics, and in the December edition, a research team led by Dr. Patrick Cossette, from the Universit?© de Montr?©al Hospital Research Centre (CRCHUM) and Associate Professor, Universit?© de Montr?©al (U de M), has demonstrated that this syndrome is caused by a newly found mutation in the AP1S1 gene.
MEDNIK syndrome was discovered in a group of families in Quebec from the Kamouraska region, sharing a common ancestor, suspected from clinical manifestations showing striking similarities to those of a similar syndrome. Caused by a mutation in the AP1S1 gene, this syndrome is characterized by mental retardation, enteropathy, deafness, and peripheral neuropathy, ichthyosis, and keratodermia (MEDNIK). ''Our observations strongly suggest that MEDNIK Syndrome is caused by impaired development of various neural networks, including the spinal chord (ataxia and neuropathy), the inner ear (sensorineural deafness) and possibly the brain (microcephaly and psychomotor retardation)," notes Dr. Cossette. ''Disruption of the AP1S1 gene in humans may be associated with more widespread perturbation in the development of various organs, including the gut and the skin. These results suggest interesting avenues for both basic and clinical research to improve our understanding of the mechanisms underlying MEDNIK and related genetic neurocutaneous syndromes."
By using zebrafish as an animal model, the team of researchers from CRCHUM, U de M, Ontario Institute for Cancer Research, McGill University, Universit?© de Sherbrooke, and Centre hospitalier r?©gional du Grand-Portage in Rivi re-du-Loup observed that the loss of the AP1S1 gene resulted in these broad defects, including severe motor deficits due to impairment of spinal cord development. By inducing the expression of the human AP1S1 gene instead of the zebrafish gene, the research team found that the normal human type could rescue these developmental deficits but not the AP1S1 gene bearing the disease-related mutation. This research appears to be the first report of a mutation in human AP1S1.
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"Why do organisms have reactions they don't use? Presumably so they have the flexibility to adapt to different conditions. One optimization situation will engage a certain set of reactions, while another situation will require a different set. It remains to be demonstrated, however, whether different conditions alone can justify the presence of all available reactions. The fact that this question is yet to be answered makes the entire problem even more attractive," Motter said.
Motter and his team used computational results to re-interpret and explain specific recent experimental results. First they gathered extensive experimental information on the metabolic networks of four different single-celled organisms: three bacteria ( H. pylori , S. aureus and E. coli ) and yeast ( S. cerevisiae ). Then the researchers built general quantitative models of the organisms that allowed them to predict cellular behavior. With those models, the researchers conducted mathematical analyses and computer experiments, simulating the organism and its metabolic function under optimal and non-optimal conditions.
They observed that for all four organisms in a typical non-optimal state, all utilizable reactions in the metabolic network, with a few exceptions, were active. In contrast, when the four organisms were growing at their optimal rate, each of them spontaneously silenced a large number of metabolic reactions. The number of active reactions, around 300, was the same for all four, despite differences in the size and complexity of each organism's genome and metabolic network. And the number stayed around 300 for a variety of quite different optimization scenarios.
"Mathematical abstraction of the problem suggests that spontaneous shutdown may not be limited to metabolic networks," said Nishikawa, who led the mathematical part of the effort. "What appears to be essential for this phenomenon is that a complex network that is under constraints and locally in balance is 'trying' to optimize its function. There are other important systems, like transportation networks, where the same type of analyses could be useful."
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