Description of combined ARHSP/JALS phenotype in some patients with SPG11 mutations

Khani, Marzieh; Shamshiri, Hosein; Fatehi, Farzad; Rohani, Mohammad; Ashtiani, Bahram Haghi; Akhoundi, Fahimeh Haji; Alavi, Afagh; Moazzeni, Hamidreza; Taheri, Hanieh; Ghani, Mina Tolou; Javanparast, Leila; Hashemi, Seyyed Saleh; Haji‐Seyed‐Javadi, Ramona; Heidari, Mahnaz; Nafissi, Shahriar; Elahi, Elahe

doi:10.1002/mgg3.1240

Cited by 7 publications

(4 citation statements)

References 53 publications

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“…This possibility is negated by observation of sensory indications in the MND‐227 patients and the absence of sensory indications in all forms of SMA. All in all, the clinical and genetic findings pertaining to MND‐227 patients are yet another indication of the complexities and overlaps amongst various neurological diseases [7, 50–53]. Here, these issues are imperfectly resolved by designating the name “non‐Kennedy SBMA” to the disease MND‐227.…”

Section: Discussionmentioning

confidence: 99%

Identification of UBA1 as the causative gene of an X‐linked non‐Kennedy spinal–bulbar muscular atrophy

Khani

Nafissi

Shamshiri

et al. 2022

Euro J of Neurology

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Background and purpose Spinal–bulbar muscular atrophy (SBMA) (Kennedy's disease) is a motor neuron disease. Kennedy's disease is nearly exclusively caused by mutations in the androgen receptor encoding gene (AR). The results of studies aimed at identification of the genetic cause of a disease that best approximates SBMA in a pedigree (four patients) without mutations in AR are reported. Methods Clinical investigations included thorough neurological and non‐neurological examinations and testing. Genetic analysis was performed by exome sequencing using standard protocols. UBA1 mutations were modeled on the crystal structure of UBA1. Results The clinical features of the patients are described in detail. A missense mutation in UBA1 (c.T1499C; p.Ile500Thr) was identified as the probable cause of the non‐Kennedy SBMA in the pedigree. Like AR, UBA1 is positioned on chromosome X. UBA1 is a highly conserved gene. It encodes ubiquitin‐like modifier activating enzyme 1 (UBA1) which is the major E1 enzyme of the ubiquitin–proteasome system. Interestingly, UBA1 mutations can also cause infantile‐onset X‐linked spinal muscular atrophy (XL‐SMA). The mutation identified here and the XL‐SMA causative mutations were shown to affect amino acids positioned in the vicinity of UBA1's ATP binding site and to cause structural changes. Conclusion UBA1 was identified as a novel SBMA causative gene. The gene affects protein homeostasis which is one of most important components of the pathology of neurodegeneration. The contribution of this same gene to the etiology of XL‐SMA is discussed.

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Section: Discussionmentioning

confidence: 99%

Identification of UBA1 as the causative gene of an X‐linked non‐Kennedy spinal–bulbar muscular atrophy

Khani

Nafissi

Shamshiri

et al. 2022

Euro J of Neurology

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“…SPG11 could play a role in multiple processes, including lysosome trafficking, cholesterol transport, autophagy, and calcium homeostasis. ALS's SPG11 mutations (such as c.704_705delAT and c.5199delA) may be associated with a lack of thinned corpus callosum and cognitive and ocular abnormalities [89,90]. NIPA Magnesium Transporter 1 (NIPA1) was initially associated with Prader-Willi/Angelman syndrome 1 or Type 6 HSP, but it may also impact ALS [91][92][93].…”

Section: Genes Involved In Protein Traffickingmentioning

confidence: 99%

Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy

Bagyinszky

Hulme

2023

Cells

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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease affecting the upper and lower motor neurons, leading to muscle weakness, motor impairments, disabilities and death. Approximately 5–10% of ALS cases are associated with positive family history (familial ALS or fALS), whilst the remainder are sporadic (sporadic ALS, sALS). At least 50 genes have been identified as causative or risk factors for ALS. Established pathogenic variants include superoxide dismutase type 1 (SOD1), chromosome 9 open reading frame 72 (c9orf72), TAR DNA Binding Protein (TARDBP), and Fused In Sarcoma (FUS); additional ALS-related genes including Charged Multivesicular Body Protein 2B (CHMP2B), Senataxin (SETX), Sequestosome 1 (SQSTM1), TANK Binding Kinase 1 (TBK1) and NIMA Related Kinase 1 (NEK1), have been identified. Mutations in these genes could impair different mechanisms, including vesicle transport, autophagy, and cytoskeletal or mitochondrial functions. So far, there is no effective therapy against ALS. Thus, early diagnosis and disease risk predictions remain one of the best options against ALS symptomologies. Proteomic biomarkers, microRNAs, and extracellular vehicles (EVs) serve as promising tools for disease diagnosis or progression assessment. These markers are relatively easy to obtain from blood or cerebrospinal fluids and can be used to identify potential genetic causative and risk factors even in the preclinical stage before symptoms appear. In addition, antisense oligonucleotides and RNA gene therapies have successfully been employed against other diseases, such as childhood-onset spinal muscular atrophy (SMA), which could also give hope to ALS patients. Therefore, an effective gene and biomarker panel should be generated for potentially “at risk” individuals to provide timely interventions and better treatment outcomes for ALS patients as soon as possible.

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“…Routine WES analysis identified the disease-causing SNVs in 35 probands [Khani et al, 2020;Hashemi et al, 2021;Pashaei et al, 2021;Rahimi Bidgoli et al, 2021;Davarzani et al, 2022;Hashemi et al, 2022;Ghasemi et al, 2023;Sadr et al, 2023a, b] (results of 10 families have not been published, yet). CNV analysis of HSP-causing genes for the remaining 35 probands identified the existence of CNV just in one proband (total 1/70; ~1.5% and 1/ 35; ~3% in this study).…”

Section: Genetic Findingsmentioning

confidence: 99%

Copy Number Variations in Hereditary Spastic Paraplegia-Related Genes: Evaluation of an Iranian Hereditary Spastic Paraplegia Cohort and Literature Review

Ghasemi¹,

Sadr²,

Babanejad³

et al. 2023

Mol Syndromol

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Introduction: In human genetic disorders, copy number variations (CNVs) are considered a considerable underlying cause. CNVs are generally detected by array-based methods but can also be discovered by read-depth analysis of whole-exome sequencing (WES) data. We performed WES-based CNV identification in a cohort of 35 Iranian families with hereditary spastic paraplegia (HSP) patients. Methods: Thirty-five patients whose routine single-nucleotide variants (SNVs) and insertion/deletion analyses from exome data were unrevealing underwent a pipeline of CNV analysis using the read-depth detection method. Subsequently, a comprehensive search about the existence of CNVs in all 84 known HSP-causing genes was carried out in all reported HSP cases, so far. Results and Discussion: CNV analysis of exome data indicated that 1 patient harbored a heterozygous deletion in exon 17 of the SPAST gene. Multiplex ligation-dependent probe amplification analysis confirmed this deletion in the proband and his affected father. Literature review demonstrated that, to date, pathogenic CNVs have been identified in 30 out of 84 HSP-causing genes (∼36%). However, CNVs in only 17 of these genes were specifically associated with the HSP phenotype. Among them, CNVs were more common in L1CAM, PLP1, SPAST, SPG7, SPG11, and REEP1 genes. The identification of the CNV in 1 of our patients suggests that WES allows the detection of both SNVs and CNVs from a single method without additional costs and execution time. However, because of intrinsic issues of WES in the detection of large rearrangements, it may not yet be exploited to replace the CNV detection methods in standard clinical practice.

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Description of combined ARHSP/JALS phenotype in some patients with SPG11 mutations

Cited by 7 publications

References 53 publications

Identification of UBA1 as the causative gene of an X‐linked non‐Kennedy spinal–bulbar muscular atrophy

Identification of UBA1 as the causative gene of an X‐linked non‐Kennedy spinal–bulbar muscular atrophy

Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy

Copy Number Variations in Hereditary Spastic Paraplegia-Related Genes: Evaluation of an Iranian Hereditary Spastic Paraplegia Cohort and Literature Review

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