scholarly journals Extensive In Silico Analysis of ATL1 Gene: Discovered Five Mutations that may Cause Hereditary Spastic Paraplegia Type 3A

2019 ◽  
Author(s):  
Mujahed I. Mustafa ◽  
Naseem S. Murshed ◽  
Abdelrahman H. Abdelmoneim ◽  
Miysaa I. Abdelmageed ◽  
Nafisa M. Elfadol ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Drug Response ◽  
3D Structure ◽  
Muscle Stiffness ◽  
Structural Level ◽  
Translational Bioinformatics ◽  
Spastic Paraplegia ◽  
Genomic Biomarkers ◽  
Analysis Tools ◽  
The Impact

ABSTRACTBACKGROUNDHereditary spastic paraplegia type 3A (SPG3A) is a neurodegenerative disease inherited type of Hereditary spastic paraplegia (HSP). It is the second most frequent type of HSP; which Characterized by muscle stiffness with paraplegia and early-onset of symptoms. This is the first translational bioinformatics analysis in a coding region of ATL1 gene which aims to categorize nsSNPs to be used as genomic biomarkers; also it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.METHODSThe raw data of ATL1 gene were retrieved from dbSNP database, and then run into numerous computational analysis tools. Additionally; we submitted the common six deleterious outcomes from the previous functional analysis tools to I-mutant 3.0, and MUPro respectively, to investigate their effect on structural level. The 3D structure of ATL1 was predicted by RaptorX and modeled using UCSF Chimera to compare the differences between the native and the mutant amino acids.RESULTSFive nsSNPs out of 249 were classified as the most deleterious (rs746927118, rs979765709, rs119476049, rs864622269, rs1242753115).CONCLUSIONSIn this study the impact of nsSNPs in the ATL1 gene was investigated by various bioinformatics tools, that revealed five nsSNPs (V67F, T120I, R217Q, R495W and G504E) are deleterious SNPs, which have a functional impact on ATL1 protein; and therefore, can be used as genomic biomarkers specifically before 4 years old; also it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.

scholarly journals Extensive In Silico Analysis of ATL1 Gene : Discovered Five Mutations That May Cause Hereditary Spastic Paraplegia Type 3A

Scientifica ◽  
2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Mujahed I. Mustafa ◽  
Naseem S. Murshed ◽  
Abdelrahman H. Abdelmoneim ◽  
Miyssa I. Abdelmageed ◽  
Nafisa M. Elfadol ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
In Silico ◽  
Computational Analysis ◽  
3D Structure ◽  
Gene Mutations ◽  
In Silico Analysis ◽  
Structural Level ◽  
Spastic Paraplegia ◽  
Analysis Tools ◽  
The Impact

Background. Hereditary spastic paraplegia type 3A (SPG3A) is a neurodegenerative disease inherited type of Hereditary spastic paraplegia (HSP). It is the second most frequent type of HSP which is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. SPG3A gene mutations and the phenotype-genotype correlations have not yet been recognized. The aim of this work was to categorize the most damaging SNPs in ATL1 gene and to predict their impact on the functional and structural levels by several computational analysis tools. Methods. The raw data of ATL1 gene were retrieved from dbSNP database and then run into numerous computational analysis tools. Additionally; we submitted the common six deleterious outcomes from the previous functional analysis tools to I-mutant 3.0 and MUPro, respectively, to investigate their effect on the structural level. The 3D structure of ATL1 was predicted by RaptorX and modeled using UCSF Chimera to compare the differences between the native and the mutant amino acids. Results. Five nsSNPs out of 249 were classified as the most deleterious (rs746927118, rs979765709, rs119476049, rs864622269, and rs1242753115). Conclusions. In this study, the impact of nsSNPs in the ATL1 gene was investigated by various in silico tools that revealed five nsSNPs (V67F, T120I, R217Q, R495W, and G504E) are deleterious SNPs, which have a functional impact on ATL1 protein and, therefore, can be used as genomic biomarkers specifically before 4 years of age; also, it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.

scholarly journals Increased baroreceptor sensitivity in a patient with hereditary spastic paraplegia – type SPG11

2018 ◽  
Vol 4 (1) ◽  
pp. 497-499
Author(s):  
Gerald Fischer ◽  
Sara Baumgartner Sigl ◽  
Daniel Baumgarten ◽  
Jürgen Fortin
Keyword(s):  
Cardiovascular System ◽  
Hereditary Spastic Paraplegia ◽  
Baroreflex Sensitivity ◽  
Sinus Bradycardia ◽  
Heart Rhythm ◽  
Spastic Paraplegia ◽  
Baroreceptor Sensitivity ◽  
Clinical Routine ◽  
Impedance Cardiogram ◽  
The Impact

AbstractAn 18 years old male patient was diagnosed with genetically confirmed hereditary spastic paraplegia of type SPG11 - a rare disease of neurodegeneration. During normal clinical routine investigation, he presented with a moderate sinus bradycardia. The function of the cardiovascular system was investigated by recording electrocardiogram, impedance cardiogram and continuous blood pressure non-invasively. Cardiac function appeared normal in all modalities. Baroreflex sensitivity was strongly increased by a factor of 2.8. Results indicate that further to hyperactivity of deep tendon reflexes, also the responsiveness regarding control of heart rhythm by baroreceptors is significantly increased. This finding provides evidence for the impact of a neurological disorder onto the cardiovascular system and its autonomic control.

scholarly journals Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking

2020 ◽  
Vol 29 (2) ◽  
pp. 320-334 ◽  
Author(s):  
Robert Behne ◽  
Julian Teinert ◽  
Miriam Wimmer ◽  
Angelica D’Amore ◽  
Alexandra K Davies ◽  
...  
Keyword(s):  
Protein Complex ◽  
Protein Trafficking ◽  
Hereditary Spastic Paraplegia ◽  
Adaptor Protein ◽  
Spastic Paraplegia ◽  
Childhood Onset ◽  
Trans Golgi Network ◽  
Wide Range ◽  
Golgi Network ◽  
The Impact

Abstract Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3–5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.

Gait Patterns in Hereditary Spastic Paraplegia

2006 ◽  
Vol 37 (01) ◽  
Author(s):  
L Döderlein ◽  
D Metaxiotis ◽  
S Wolf ◽  
F Braatz
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Gait Patterns

SPG10 in German families with hereditary spastic paraplegia

2006 ◽  
Vol 33 (S 1) ◽  
Author(s):  
R. Schüle ◽  
M. Auer-Grumbach ◽  
J. Kassubek ◽  
S. Klimpe ◽  
T. Klopstock ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia

Evolocumab (PCSK9 Inhibitor) in Hereditary Spastic Paraplegia Type 5

2020 ◽  
Author(s):  
Ying Fu ◽  
Xiang Lin ◽  
Yi-Jun Chen ◽  
Lu-Lu Lai ◽  
Yi Lin ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Pcsk9 Inhibitor

Thalamic atrophy in patients with pure hereditary spastic paraplegia type 4

2021 ◽  
Author(s):  
Francisco J. Navas-Sánchez ◽  
Alberto Fernández-Pena ◽  
Daniel Martín de Blas ◽  
Yasser Alemán-Gómez ◽  
Luís Marcos-Vidal ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia

Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes

2021 ◽  
Author(s):  
Katiane R. Servelhere ◽  
Thiago Junqueira Ribeiro Rezende ◽  
Fabrício Diniz Lima ◽  
Mariana Rabelo Brito ◽  
Renan Flávio França Nunes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Damage ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia
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