Novel mutations in the SPAST gene cause hereditary spastic paraplegia

Zhu, Zeyu; Zhang, Chao; Zhao, Guohua; Liu, Qing; Zhong, Ping; Zhang, Mei; Tang, Weiguo; Zhan, Feixia; Tian, Wen; Wang, Yan; Yin, Kaili; Huang, Xiaojun; Jiang, Jingwen; Liu, Xiaoli; Liu, Shihua; Zhou, Haiyan; Luan, Xinghua; Tang, Huidong; Wang, Ying; Chen, Shengdi; Cao, Li

doi:10.1016/j.parkreldis.2019.11.007

Cited by 10 publications

(14 citation statements)

References 17 publications

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“…The genomic DNA of the proband and her parents were extracted using a standardized phenol/chloroform extraction method. Whole exome sequencing was performed as previously described ( Zhu et al, 2019 ). Sanger sequencings was applied to validate variants of the LAMC3 gene in the proband and her parents.…”

Section: Methodsmentioning

confidence: 99%

Variants in LAMC3 Causes Occipital Cortical Malformation

Qian

Zhu

et al. 2021

Front. Genet.

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Occipital cortical malformation (OCCM) is a disease caused by malformations of cortical development characterized by polymicrogyria and pachygyria of the occipital lobes and childhood-onset seizures. The recessive or complex heterozygous variants of the LAMC3 gene are identified as the cause of OCCM. In the present study, we identified novel complex heterozygous variants (c.470G > A and c.4030 + 1G > A) of the LAMC3 gene in a Chinese female with childhood-onset seizures. Cranial magnetic resonance imaging was normal. Functional experiments confirmed that both variant sites caused premature truncation of the laminin γ3 chain. Bioinformatics analysis predicted 10 genes interacted with LAMC3 with an interaction score of 0.4 (P value = 1.0e–16). The proteins encoded by these genes were mainly located in the basement membrane and extracellular matrix component. Furthermore, the biological processes and molecular functions from gene ontology analysis indicated that laminin γ3 chain and related proteins played an important role in structural support and cellular processes through protein-containing complex binding and signaling receptor binding. KEGG pathway enrichment predicted that the LAMC3 gene variant was most likely to participate in the occurrence and development of OCCM through extracellular matrix receptor interaction and PI3K-Akt signaling pathway.

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Section: Methodsmentioning

confidence: 99%

Variants in LAMC3 Causes Occipital Cortical Malformation

Qian

Zhu

et al. 2021

Front. Genet.

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“…COS-7 (SCSP-508) cells were purchased from the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences. COS-7 cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM)/F12 (Gibco; Thermo Fisher Scientific, Inc.) supplemented with 10% fetal bovine serum (FBS) (Gibco; Thermo Fisher Scientific, Inc.) in a 37°C and 5% CO 2 incubator. Half of the culture media was replaced every 3 days.…”

Section: Methodsmentioning

confidence: 99%

“…Hippocampal neurons of newborn Sprague-Dawley rat pups were performed as previously described. 28 , 29 Hippocampi were dissected and obtained by 0.125% trypsin (Thermo Fisher Scientific, Inc.), and then plated onto poly-D-lysine-coated glass coverslips (Thermo Fisher Scientific, Inc.), at a density of 1 x 10 4 cells cm 2 . Neuronal cultures were maintained in Neurobasal-A medium (Gibco; Thermo Fisher Scientific, Inc.) containing 2% B27 (Gibco; Thermo Fisher Scientific, Inc.) in a humidified incubator.…”

Section: Methodsmentioning

confidence: 99%

“… 1 Mutations in the gene encoding for SPAST (SPG4) are the most common cause of autosomal dominant HSP. 2 Spastin belongs to the ATPase associated with various cellular activities (AAA) protein family and its activity is associated with diverse cellular processes. SPG4 gene translates to two spastin isoforms, M1 (68 kDa) and M87 (60 kDa).…”

Section: Introductionmentioning

confidence: 99%

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Different fusion tags affect the activity of ubiquitin overexpression on spastin protein stability

et al. 2021

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Spastin is one of the proteins which lead to hereditary spastic paraplegia (HSP), whose dysfunction towards microtubule severing and membrane transporting is critically important. The present study is to elucidate the mechanisms of the protein stability regulation of spastin. The ubiquitin encoding plasmids are transfected into COS-7 cells with different fusion tags including Green Fluorescent Protein (GFP), mCherry and Flag. The expression level of spastin was detected, microtubule severing activity and neurite outgrowth were quantified. The data showed that ubiquitin overexpression significantly induced the decreased expression of spastin, suppressed the activity of microtubule severing in COS-7 cells and inhibited the promoting effect on neurite outgrowth in cultured hippocampal neurons. Furthermore, when modulating the overexpression experiments of ubiquitin, it was found that relatively small tag like Flag, but not large tags such as GFP or mCherry fused with ubiquitin, retained the activity on spastin stability. The present study investigated the effects of small/large tags addition to ubiquitin and the novel mechanisms of post-transcriptional modifications of spastin on regulating neurite outgrowth, in the attempt to experimentally elucidate the mechanisms that control the level or stability of spastin in hereditary spastic paraplegia.

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“…Among them, hereditary spastic paraplegia type 4 (SPG4) is the most frequent subtype of AD-HSP (SPG4, MIM: 182601) and comprises 45% of HSP. As the most frequent causal gene of SPG4, the SPG4/SPAST (protein: Spastin) gene accounts for approximately 40% of AD pedigrees and 20% of sporadic cases, respectively (13). In addition, more than 45 autosomal recessive (AR)-HSP subtypes have been identified (including SPG5, SPG7, SPG11, SPG14, and SPG15, etc.)…”

Section: Introductionmentioning

confidence: 99%

A novel variant of SPAST in a pedigree with pure hereditary spastic paraplegia in Yunnan Province

Shen¹,

Zhang²,

Li³

et al. 2022

Ann Transl Med

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Background: Hereditary spastic paraplegia (HSP) is a rare group of genetically heterogeneous, neurodegenerative disorders. The aim of this study was to identify pathological candidate genes and variants in a large pedigree cohort of 11 purely HSP patients in Yunnan Province.Methods: Whole-exome sequencing (WES) was applied to 2 HSP patients and 1 control patient to screen out the candidate gene variants. Then, filtration and verification of these pathological variants were performed by Sanger sequencing.Results: After the raw data were filtered, two genes with novel variations (SPAST: c.1510 C>T, p.Gln504X, RefSeq.NM_199436; DNAJC16: c.718 C>T, p.Q240X, Ref Seq NM_015291) were identified. The accession numbers of the genes in the ClinVar database were SCV001573094 and SCV001573804, respectively. One gene with a reported single nucleotide polymorphism (CPT1C: rs150853576) was filtered as a candidate variant. Using Sanger sequencing, the novel SPAST gene (protein: Spastin) variant leading to a predicted premature termination and an 18% deletion of the SPAST/spastic paraplegia type 4 (SPG4) protein was confirmed to exist only in affected individuals. The candidate CPT1C and DNAJC16 variants were verified in almost all HSP patients, with one exception.Conclusions: Considering that the clinical symptoms and time of onset of HSP are highly heterogeneous, the SPAST as a genotype-phenotype cosegregated variant might be the causative gene of this pedigree, and the other two variants might present cumulative risks to the occurrence and progression of HSP. These three candidate genes with or without novel variants may be potential contributors to disease onset, and therefore useful diagnostic and therapeutic biomarkers. Further research is required to confirm the functions of these genes.

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Novel mutations in the SPAST gene cause hereditary spastic paraplegia

Cited by 10 publications

References 17 publications

Variants in LAMC3 Causes Occipital Cortical Malformation

Variants in LAMC3 Causes Occipital Cortical Malformation

Different fusion tags affect the activity of ubiquitin overexpression on spastin protein stability

A novel variant of SPAST in a pedigree with pure hereditary spastic paraplegia in Yunnan Province

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