Mutational spectrum of the SPAST and ATL1 genes in Korean patients with hereditary spastic paraplegia

Park, Hyunwoong; Kang, Seong Ho; Park, Seungman; Kim, So Yeon; Seo, Soo Hyun; Lee, Seung Jun; Lee, Jung Ae; Cho, Sung Im; Sung, Jung‐Joon; Lee, Kwang Woo; Kim, Ji Yeon; Park, Sung Sup; Seong, Moon-Woo

doi:10.1016/j.jns.2015.07.024

Cited by 17 publications

(11 citation statements)

References 25 publications

(33 reference statements)

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“…We note that spastin mutants that are deficient in oligomerization could still bind microtubules through a stretch of residues in the linker that connects the AAA and MIT 3,6,7,13,64 domains and thus have a toxic gain of function on the microtubule cytoskeleton. Interestingly, mutations in the Arg finger R499 have been associated with early onset HSP 41,52,53,59,65–68 , possibly suggesting a dominant negative effect of this mutation. The Walker B residue E442 is the other strong candidate for a dominant negative mechanism, however not enough phenotypic data are currently available for this HSP mutation.…”

Section: Resultsmentioning

confidence: 99%

An allosteric network in spastin couples multiple activities required for microtubule severing

Sandate

Szyk

Zehr

et al. 2019

Nat Struct Mol Biol

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The AAA+ ATPase spastin remodels microtubule arrays through severing, and its mutation is the most common cause of hereditary spastic paraplegias (HSP). Polyglutamylation of the tubulin C-terminal tail recruits spastin to microtubules and modulates severing activity. Here, we present a ~3.2 Å resolution cryo-EM structure of the Drosophila melanogaster spastin hexamer with a polyglutamate peptide bound in its central pore. Two electropositive loops arranged in a double-helical staircase coordinate the substrate sidechains. The structure reveals how concurrent nucleotide and substrate binding organizes the conserved spastin pore loops into an ordered network that is allosterically coupled to oligomerization, and suggests how tubulin tail engagement activates spastin for microtubule disassembly. This allosteric coupling may apply generally in organizing AAA+ protein translocases into their active conformations. We show that this allosteric network is essential for severing and is a hotspot for HSP mutations.

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Section: Resultsmentioning

confidence: 99%

An allosteric network in spastin couples multiple activities required for microtubule severing

Sandate

Szyk

Zehr

et al. 2019

Nat Struct Mol Biol

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“…In addition, R239C ( n = 31) [6, 9, 11, 13, 15, 17, 21, 22, 27–29, 31, 32, 36, 39, 45, 51, 53, 54, 56] and R495W ( n = 14) [15–17, 21, 32, 36, 43, 50, 52, 54] mutations were the most commonly reported mutations in all studied families. Zhao et al reported that the three families with R239C mutations were not apparently related and haplotype analysis did not exclude a distant founder effect [6].…”

Section: Discussionmentioning

confidence: 97%

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Zhao

Liu

2017

Transl Neurodegener

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BackgroundThe hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. Approximately 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear. The study aims to investigate the genotype-phenotype correlation in SPG3A patients.MethodsWe performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.ResultsMost HSPs-SPG3A patients exhibited an early age at onset (AAO) of <10 years old, and showed an autosomal dominant pure spastic paraplegia. We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes, with distal atrophy being the most common complicated symptom. The AAO of each mutation group was not statistically significant (P > 0.05). The mutational spectrum associated with ATL1 gene mutation is wide, and most mutations are missense mutations, but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.ConclusionsOur findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients. We also find that exons 4, 7, 8 and 12 are mutation hotspots in ATL1 gene.Electronic supplementary materialThe online version of this article (doi:10.1186/s40035-017-0079-3) contains supplementary material, which is available to authorized users.

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“…Nevertheless, we must be cautious about the small number of examined Czech patients, but no other data are available regarding Czech HSP patients, because we are the only facility performing DNA diagnostics for HSP in the Czech Republic. Similarly, a low occurrence of ATL1 causative variants among HSP patients has been recently described in various European and Asian populations (Kim et al., ; Lu et al., ; Elert‐Dobkowska et al., ; Park et al., ).…”

Section: Discussionmentioning

confidence: 66%

Disease‐Causing Variants in the ATL1 Gene Are a Rare Cause of Hereditary Spastic Paraplegia among Czech Patients

Meszarosova

Grečmalová

Brazdilova

et al. 2017

Annals of Human Genetics

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Variants in the ATL1 gene have been repeatedly described as the second most frequent cause of hereditary spastic paraplegia (HSP), a motor neuron disease manifested by progressive lower limb spasticity and weakness. Variants in ATL1 have been described mainly in patients with early onset HSP. We performed Sanger sequencing of all coding exons and adjacent intron regions of the ALT1 gene in 111 Czech patients with pure form of HSP and additional Multiplex-Ligation Probe Analysis (MLPA) testing targeting the ATL1 gene in 56 of them. All patients except seven were previously tested by Sanger sequencing of the SPAST gene with negative results. ATL1 diagnostic testing revealed only five missense variants in the ATL1 gene. Four of them are novel, but we suppose only two of them to be pathogenic and causal. The remaining variants are assumed to be benign. MLPA testing in 56 of sequence variant negative patients revealed no gross deletion in the ATL1 gene. Variants in the ATL1 gene are more frequent in patients with early onset HSP, but in general the occurrence of pathogenic variants in the ATL1 gene is low in our cohort, less than 4.5% and less than 11.1% in patients with onset before the age of ten. Variants in the ATL1 gene are a less frequent cause of HSP among Czech patients than has been previously reported among other populations.

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Mutational spectrum of the SPAST and ATL1 genes in Korean patients with hereditary spastic paraplegia

Cited by 17 publications

References 25 publications

An allosteric network in spastin couples multiple activities required for microtubule severing

An allosteric network in spastin couples multiple activities required for microtubule severing

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Disease‐Causing Variants in the ATL1 Gene Are a Rare Cause of Hereditary Spastic Paraplegia among Czech Patients

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