PloS one, 2014-08, Vol.9 (8), p.e104790-e104790
2014
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- Autor(en) / Beteiligte
- Titel
- PMCA4 (ATP2B4) mutation in familial spastic paraplegia
- Ist Teil von
- PloS one, 2014-08, Vol.9 (8), p.e104790-e104790
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2014
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. In this study, we identified a novel missense mutation (c.803G>A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP using whole-exome sequencing and confirmed with Sanger sequencing. This mutation co-segregated with the phenotype in the six family members studied and is predicted to be pathogenic when multiple deleteriousness predictions were combined. This novel R268Q mutation was not present in over 7,000 subjects in public databases, and over 1,000 Han Chinese in our database. Prediction of potential functional consequence of R268Q mutation on PMCA4 by computational modeling revealed that this mutation is located in protein aggregation-prone segment susceptible to protein misfolding. Analysis for thermodynamic protein stability indicated that this mutation destabilizes the PMCA4 protein structure with higher folding free energy. As PMCA4 functions to maintain neuronal calcium homeostasis, our result showed that calcium dysregulation may be associated with the pathogenesis of FSP.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0104790Titel-ID: cdi_plos_journals_1553135315
- Format
- –
- Schlagworte
- Asian Continental Ancestry Group - genetics, Ataxia, Base Sequence, Bioinformatics, Biology and Life Sciences, Ca2+-transporting ATPase, Calcium, Calcium homeostasis, Computational neuroscience, Deoxyribonucleic acid, DNA, DNA sequencing, Exome - genetics, Free energy, Gene sequencing, Genes, Genes, Dominant - genetics, Genetic aspects, Genomes, Heredity, Homeostasis, Humans, Medicine, Medicine and Health Sciences, Missense mutation, Models, Genetic, Molecular Sequence Data, Mutation, Mutation, Missense - genetics, Neural networks, Neurology, Paralysis, Paraplegia, Pathogenesis, Pedigree, Phenotype, Phenotypes, Plasma, Plasma Membrane Calcium-Transporting ATPases - genetics, Predictions, Protein Folding, Protein interaction, Protein structure, Proteins, Psychiatry, Sequence Analysis, DNA, Signal transduction, Spastic paraplegia, Spastic Paraplegia, Hereditary - genetics, Spasticity, Stability analysis, Studies