title: PMCA4 (ATP2B4) mutation in familial spastic paraplegia.
abstract: 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.
authors.affiliation: Department of Psychiatry, University of Hong Kong, Hong Kong, P. R. China; Centre for Reproduction, Development and Growth, University of Hong Kong, Hong Kong, P. R. China; Centre for Genomic Sciences, University of Hong Kong, Hong Kong, P. R. China.
authors.forename: Miaoxin
authors.initials: M
authors.lastname: Li
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong, Hong Kong, P. R. China; Research Centre of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong, Hong Kong, P. R. China.
authors.forename: Philip Wing-Lok
authors.initials: PW
authors.lastname: Ho
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong, Hong Kong, P. R. China.
authors.forename: Shirley Yin-Yu
authors.initials: SY
authors.lastname: Pang
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong, Hong Kong, P. R. China.
authors.forename: Zero Ho-Man
authors.initials: ZH
authors.lastname: Tse
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong, Hong Kong, P. R. China.
authors.forename: Michelle Hiu-Wai
authors.initials: MH
authors.lastname: Kung
authors.affiliation: Department of Psychiatry, University of Hong Kong, Hong Kong, P. R. China; Centre for Reproduction, Development and Growth, University of Hong Kong, Hong Kong, P. R. China; Centre for Genomic Sciences, University of Hong Kong, Hong Kong, P. R. China.
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong, Hong Kong, P. R. China; Research Centre of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong, Hong Kong, P. R. China.
authors.forename: Shu-Leong
authors.initials: SL
authors.lastname: Ho
mesh_terms: D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D059472:Exome / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics*; D017510:Protein Folding; D017422:Sequence Analysis, DNA; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
chemical_list: D053499:Plasma Membrane Calcium-Transporting ATPases