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.
Highlights
Familial spastic paraplegia (FSP) is a clinically and genetically heterogeneous group of diseases characterized by progressive lower limb spasticity and weakness, and is classified according to phenotype, mode of inheritance and the mutated gene [1]
We describe a Chinese family with autosomal dominant FSP
PMCA4 belongs to the family of plasma membrane Ca2+ATPases consisting of 4 isoforms with dozens of variants generated by alternative RNA splicing [14]
Summary
Familial spastic paraplegia (FSP) is a clinically and genetically heterogeneous group of diseases characterized by progressive lower limb spasticity and weakness, and is classified according to phenotype, mode of inheritance and the mutated gene [1]. Pure FSP is characterized by progressive lower limb weakness and spasticity and may be associated with urinary urgency, mild impairment of vibration sense and proprioception. Complex FSP is characterized by additional manifestations such as cognitive impairment, epilepsy, cerebellar ataxia, extrapyramidal disturbances, optic atrophy and peripheral neuropathy. Different mutations in the same gene can cause either pure or complex FSP, and intrafamilial phenotypic variability is high, greatly complicating the genetic diagnosis of FSP. Seventy-one forms of FSP (SPG1 to SPG48) have been described involving many gene loci [3], with 20 or more loci associated with autosomal dominant FSP [2]. The associated genes have been reported to be involved in organelle and microtubule dynamics, endoplasmic reticulum homoeostasis, transport, and signal transduction
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