PMCA4 (ATP2B4) mutation in familial spastic paraplegia

Miaoxin Li, Philip Wing Lok Ho, Shirley Yin Yu Pang, Zero Ho Man Tse, Michelle Hiu Wai Kung, Pak Chung Sham, Shu Leong Ho

Research output: Journal article publicationJournal articleAcademic researchpeer-review

28 Citations (Scopus)


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.

Original languageEnglish
Article numbere104790
JournalPLoS ONE
Issue number8
Publication statusPublished - 13 Aug 2014
Externally publishedYes

ASJC Scopus subject areas

  • General


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