A new model for a rare disease
Oeiras, 15.05.12
Among the disorders tested in newborn screenings (known in Portugal as “teste do pézinho”) is multiple acyl-CoA dehydrogenase deficiency or MADD, a rare metabolic disease that affects the metabolism of fatty acids. Collaboration between developmental biologists from IGC and biochemists from ITQB has now added a new tool for studying this disease, by identifying fly mutants that mimic the human disorder. The work is published in the latest issue of Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.
As often happens in science, the project was born out of chance. MADD has been one of the research targets of the Protein Biochemistry and Folding Lab for some time. On the other hand, the Early Fly Development Unit at IGC was interested in genes affecting epithelial development in fruit flies. Looking at fly mutants impaired in development, researchers came across non-viable embryos that turned out to be affected in one of the proteins (ETF:QO) that is also affected in MADD, a coincidence researchers from the two institutes realized one day over lunch. This set ITQB researchers to study the fly proteins and figure out how their structure and activity were affected in the mutants.
In humans, MADD can present itself in severe forms, leading to death, and moderate forms, the milder of which can be controlled by diet and nutritional supplements. The fly mutations would correspond to the more severe forms. In fact, sequencing of the fly mutated genes showed that the ETF:QO protein’s active site was affected, something that would render the enzyme unable to function. The non-viable fly embryos were subjected to the typical newborn screening test and the result was a metabolite pattern similar to the one of MADD patients’ blood. By identifying the molecular origins of a severe MADD-like disorder in fruit flies, researchers have now established the proof of concept for using these organisms as models for MADD, both for studying the disease and for testing new drugs.
For ITQB researcher, Claudio Gomes, who co-coordinated the project, “this article is a good example of how partnerships between associated institutions work, both by allowing expertise to merge and, most importantly, by promoting chance”.
Original Article
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, http://dx.doi.org/10.1016/j.bbadis.2012.05.003
Mutations at the flavin binding site of ETF:QO yield a MADD-like severe phenotype in Drosophila
Ema Alves a, b, Bárbara J. Henriques a, João V. Rodrigues a, Pedro Prudêncio b, Hugo Rocha c, Laura Vilarinho c, Rui G. Martinho b, d, Cláudio M. Gomes a
a Instituto Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal
b Instituto Gulbenkian de Ciência, Oeiras, Portugal
c Unidade de Rastreio Neonatal, Instituto Nacional de Saúde, Porto, Portugal
d Dept. Ciências Biomédicas e Medicina, Universidade do Algarve, Portugal
