Abstract
BackgroundHereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum.MethodsWhole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function.ResultsSpastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein.ConclusionIn this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.
Highlights
Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder
Physical examination showed that she had brisk deep tendon reflexes in all four limbs, simultaneously accompanied with obvious corticospinal tract signs (Babinski’s signs was positive), and decreased sense of pain, light touch and vibration in the lower limbs characterized with stocking pattern-distributed sensory loss
The proband had ever received some treatment on rheumatoid arthritis because of the pain in both hips and knees 26 years ago, but the uncomfortable symptom was not getting better. 9 years ago, a traumatic injury on her back further aggravated her discomfort though the cranial and cervical Magnetic resonance imaging (MRI) were both normal at that time
Summary
Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. We report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. Hereditary spastic paraplegia (HSP), called familial spastic paraparesis or Strümpell-Lorrain disease, is a group of neurodegenerative and inherited heterogeneous neurological disorders characterized by a length-dependent distal axonal degeneration of the corticospinal tracts [1]. The SPG4/ SPAST gene comprising 17 exons, identified as the 90-kb genomic region on chromosome 2 We report a novel SPAST gene mutation site (c.1710_1712delGAA) that presented in a Chinese family with HSP, significantly enriching the mutation spectrum of HSP gene
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