Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by the mutations in survival motor neuron 1 gene (SMN1). The molecular pathology of missense mutations in SMN1 is not thoroughly investigated so far. Therefore, we collected all missense mutations in the SMN1 protein, using all possible search terms, from three databases (PubMed, PMC and Google Scholar). All missense mutations were subjected to in silico pathogenicity, conservation, and stability analysis tools. We used statistical analysis as a QC measure for validating the specificity and accuracy of these tools. PolyPhen-2 demonstrated the highest specificity and accuracy. While PolyPhen-1 showed the highest sensitivity; overall, PolyPhen2 showed better measures in comparison to other in silico tools. Three mutations (D44V, Y272C, and Y277C) were identified as the most pathogenic and destabilizing. Further, we compared the physiochemical properties of the native and the mutant amino acids and observed loss of H-bonds and aromatic stacking upon the cysteine to tyrosine substitution, which led to the loss of aromatic rings and may reduce protein stability. The three mutations were further subjected to Molecular Dynamics Simulation (MDS) analysis using GROMACS to understand the structural changes. The Y272C and Y277C mutants exhibited maximum deviation pattern from the native protein as compared to D44V mutant. Further MDS analysis predicted changes in the stability that may have been contributed due to the loss of hydrogen bonds as observed in intramolecular hydrogen bond analysis and physiochemical analysis. A loss of function/structural impact was found to be severe in the case of Y272C and Y277C mutants in comparison to D44V mutation. Correlating the results from in silico predictions, physiochemical analysis, and MDS, we were able to observe a loss of stability in all the three mutants. This combinatorial approach could serve as a platform for variant interpretation and drug design for spinal muscular dystrophy resulting from missense mutations.
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PMID:Impact of missense mutations in survival motor neuron protein (SMN1) leading to Spinal Muscular Atrophy (SMA): A computational approach. 3000 96

In mammals, air is moved in and out of the lungs by a sheet of muscle called the diaphragm. When this muscle contracts air gets drawn into the lungs and as the muscle relaxes this pushes air back out. Movement of the diaphragm is controlled by a group of nerve cells called motor neurons which are part of the phrenic motor column (or PMC for short) that sits within the spinal cord. The neurons within this column work together with nerve cells in the brain to coordinate the speed and duration of each breath. For the lungs to develop normally, the neurons that control how the diaphragm contracts need to start working before birth. During development, motor neurons in the PMC cluster together and connect with other nerve cells involved in breathing. But, despite their essential role, it is not yet clear how neurons in the PMC develop and join up with other nerve cells. Now, Vagnozzi et al. show that a set of genes which make the transcription factor Hox5 control the position and organization of motor neurons in the PMC. Transcription factors work as genetic switches, turning sets of genes on and off. Vagnozzi et al. showed that removing the Hox5 transcription factors from motor neurons in the PMC changed their activity and disordered their connections with other breathing-related nerve cells. Hox5 transcription factors regulate the production of proteins called cadherins which join together neighboring cells. Therefore, motor neurons lacking Hox5 were unable to make enough cadherins to securely stick together and connect with other nerve cells. Further experiments showed that removing the genes that code for Hox5 caused mice to have breathing difficulties in the first two weeks after birth. Although half of these mutant mice were eventually able to breathe normally, the other half died within a week. These breathing defects are reminiscent of the symptoms observed in sudden infant death syndrome (also known as SIDS). Abnormalities in breathing occur in many other diseases, including sleep apnea, muscular dystrophy and amyotrophic lateral sclerosis (ALS). A better understanding of how the connections between nerve cells involved in breathing are formed, and the role of Hox5 and cadherins, could lead to improved treatment options for these diseases.
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PMID:Phrenic-specific transcriptional programs shape respiratory motor output. 3194 80