Genetic background of the hereditary spastic paraplegia phenotypes in Hungary — An analysis of 58 probands

Balicza, Péter; Grosz, Zoltán; Gonzalez, Michael; Bencsik, Renáta; Pentelényi, Klára; Gál, Anikó; Varga, Edina; Klivényi, Péter; Koller, Júlia; Züchner, Stephan; Molnár, Mária Judit

doi:10.1016/j.jns.2016.03.018

Cited by 30 publications

(21 citation statements)

References 44 publications

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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%

“…Although several large cohorts of patients with mutant ATL1 gene were reported [17, 21, 27, 29, 32, 36, 45, 50, 54, 56], a genotype-phenotype correlation still remains unclear. Here, we reanalysed the observations on 142 families and confirmed three previously reported observations.…”

Section: Discussionmentioning

confidence: 99%

“…We conducted a literature search using databases from PubMed (http://ncbi.nlm.nih.gov/pubmed) and the China National Knowledge Infrastructure (CNKI) (http://cnki.net) with the keyword “SPG3A” or “ ATL1 ”, which resulted in 51 articles describing ATL1 gene mutations [6–56]. We collected information related to the age at onset (AAO), age at examination, pure or complicated form, involvement of upper and lower limbs, Babinski signs, urinary urgency and other symptoms or signs for individually affected patients directly from relevant papers.…”

Section: Methodsmentioning

confidence: 99%

“…Currently there are more than 60 different ATL1 gene mutations described, including numerous missense, small deletion, small insertion and splice site mutations, as well as whole exon deletions [6–56]. However, the genotype-phenotype correlation remains unclear [13].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhao

Liu

2017

Transl Neurodegener

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“…This coincided with increased cellular lipid peroxidation and reduced energy production, possibly caused by defective FA trafficking to peroxisomes. Intriguingly, some ALD patients with mutations in a peroxisomal FA transporter ATP binding cassette subfamily D member 1 (ABCD1) also manifest neurologic symptoms, such as spasticity (Balicza et al, 2016;Koutsis et al, 2015;Lodhi and Semenkovich, 2014;Maris et al, 1995;Shaw-Smith et al, 2004;Zhan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III

Chang

Weigel

Ioannou

et al. 2019

Preprint

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Lipid droplets (LDs) are neutral lipid storage organelles that transfer lipids to various organelles including peroxisomes. Here, we show that the hereditary spastic paraplegia protein M1 Spastin, a membrane-bound AAA ATPase found on LDs, coordinates fatty acid (FA) trafficking from LDs to peroxisomes through two inter-related mechanisms. First, M1 Spastin forms a tethering complex with peroxisomal ABCD1 to promote LD-peroxisome contact formation. Second, M1 Spastin recruits the membrane-shaping ESCRT-III proteins IST1 and CHMP1B to LDs via its MIT domain to facilitate LD-to-peroxisome FA trafficking, possibly through IST1 and CHMP1B modifying LD membrane morphology. Furthermore, M1 Spastin, IST1 and CHMP1B are all required to relieve LDs of lipid peroxidation. M1 Spastin's dual roles in tethering LDs to peroxisomes and in recruiting ESCRT-III components to LD-peroxisome contact sites for FA trafficking may help explain the pathogenesis of diseases associated with defective FA metabolism in LDs and peroxisomes.

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Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia

Fang

Chou

Hsu

et al. 2023

Ann Clin Transl Neurol

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Objective NIPA1 mutations have been implicated in hereditary spastic paraplegia (HSP) as the cause of spastic paraplegia type 6 (SPG6). The aim of this study was to investigate the clinical and genetic features of SPG6 in a Taiwanese HSP cohort. Methods We screened 242 unrelated Taiwanese patients with HSP for NIPA1 mutations. The clinical features of patients with a NIPA1 mutation were analyzed. Minigene‐based splicing assay, RT‐PCR analysis on the patients' RNA, and cell‐based protein expression study were utilized to assess the effects of the mutations on splicing and protein expression. Results Two patients were identified to carry a different heterozygous NIPA1 mutation. The two mutations, c.316G>A and c.316G>C, are located in the 3′ end of NIPA1 exon 3 near the exon–intron boundary and putatively lead to the same amino acid substitution, p.G106R. The patient harboring NIPA1 c.316G>A manifested spastic paraplegia, epilepsy and schizophrenia since age 17 years, whereas the individual carrying NIPA1 c.316G>C had pure HSP since age 12 years. We reviewed literature and found that epilepsy was present in multiple individuals with NIPA1 c.316G>A but none with NIPA1 c.316G>C. Functional studies demonstrated that both mutations did not affect splicing, but only the c.316G>A mutation was associated with a significantly reduced NIPA1 protein expression. Interpretation SPG6 accounted for 0.8% of HSP cases in the Taiwanese cohort. The NIPA1 c.316G>A and c.316G>C mutations are associated with adolescent‐onset complex and pure form HSP, respectively. The different effects on protein expression of the two mutations may be associated with their phenotypic discrepancy.

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Genetic background of the hereditary spastic paraplegia phenotypes in Hungary — An analysis of 58 probands

Cited by 30 publications

References 44 publications

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

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

Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III

Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia

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