<i>HSP60</i>
            IS A RARE CAUSE OF HEREDITARY SPASTIC PARAPARESIS, BUT MAY ACT AS A GENETIC MODIFIER

Hewamadduma, Channa; Kirby, Janine; Kershaw, Christopher J.; Martindale, Joanne; Dalton, Ann; McDermott, Christopher J.; Shaw, Peter J.

doi:10.1212/01.wnl.0000311395.31081.70

Cited by 20 publications

(18 citation statements)

References 7 publications

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“…Previous studies have shown that the frequency of S44L in SPAST was reported to be 3.5% in normal controls versus 2.8% in SPG4 patients [6]. The polymorphism p.G563A in HSPD1 has also been reported to be an intergenic modifier for SPG4 [8]. The frequency of the p.G563A variant is 1.3% in the Danish population [31].…”

Section: Discussionmentioning

confidence: 99%

“…Two specific sequence variants resulting in changes in two adjacent amino acids (S44L and P45Q) of spastin, the protein encoded by SPAST , are known to act as modifiers of SPG4 and result in an earlier and more severe phenotype when found in trans with a mutation in SPAST [6,7]. In addition, a polymorphism (c.1688G>C/p.G563A) in HSPD1 has been reported to modify the SPG4 phenotype, causing an earlier onset of the disease symptoms [8]. In SPAST -negative AD-HSP patients, ATL1 (SPG3A) mutations are believed to be the most common causes of AD-HSPs, especially in young-onset cases (under 10 years of age) [9].…”

Section: Introductionmentioning

confidence: 99%

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Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Luo¹,

Chen²,

Zhan³

et al. 2014

Neurodegener Dis

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Background: Hereditary spastic paraplegias constitute a heterogeneous group of inherited neurodegenerative disorders. To date, there has been no systematic mutation and clinical analysis for a large group of autosomal-dominant hereditary spastic paraplegias in China. Objective: The purpose of this study was to investigate the mutation frequencies and the clinical phenotypes of Chinese spastic paraplegia patients. Methods: Direct sequencing and a multiplex ligation-dependent probe amplification assay were applied to detect the mutations of SPAST and ATL1 in 54 autosomal-dominant hereditary spastic paraplegia probands and 66 isolated cases. Next, mutations in NIPA1, KIF5A, REEP1 and SLC33A1 were detected in the negative patients. Subsets of spastic paraplegia patients were genotyped for the modifying variants. Further, detailed clinical data regarding the genetically diagnosed families were analysed. Results: Altogether, 27 families were diagnosed as SPG4, 3 as SPG3A and 1 as SPG6. No mutations in KIF5A, REEP1 or SLC33A1 were found; 9 SPAST mutations were novel. There was no p.S44L or p.P45Q variant in SPAST and no p.G563A variant in HSPD1 in either the 120 spastic paraplegia patients or the 500 controls. There was a remarkable clinical difference between the SPG4 and non-SPG4 patients and even between genders among the SPG4 patients. Non-penetrance and remarkable gender difference were observed in some SPG4 and SPG3A families. Conclusions: Our data confirm that hereditary spastic paraplegias in China represent a heterogeneous group of genetic neurodegenerative disorders in autosomal-dominant and apparently sporadic forms. Novel genotype-phenotype correlations were established.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Luo¹,

Chen²,

Zhan³

et al. 2014

Neurodegener Dis

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“…One of those defects is an X-linked recessive deafness-dystonia syndrome (Mohr-Tranebjaerg syndrome) caused by mutations in the gene encoding the deafness/dystonia protein (DDP), a component of the import machinery (119). Another autosomal dominant form of hereditary spastic paraplegia is caused by mutations in the import chaperon HSP60, presumably affecting protein refolding (120,121).…”

Section: Defects In Mitochondrial Import and Morphologymentioning

confidence: 99%

PGC‐1α activation as a therapeutic approach in mitochondrial disease

Wenz

2009

IUBMB Life

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SummaryMitochondria play a central role in cellular homeostasis. Hence, mitochondrial dysfunction resulting in impaired ATP supply is detrimental to cell viability and causes severe and often fatal disorders. Current treatment of these mitochondrial disorders is limited and mostly addresses the symptoms, but not the deficiency itself. Recent work in cell and animal models of mitochondrial disease shows that increased mitochondrial biogenesis can boost residual OXPHOS capacity and thereby prevent the bioenergetic crisis. In animal models, this strategy results in increased health and lifespan. Here, I review which mitochondrial processes are affected in known mitochondrial disorders and discuss why PGC-1a mediated mitochondrial biogenesis offers a promising venue for treatment of mitochondrial disorders.

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“…The p.Gly563Ala variation in HSPD1, previously reported to have a modifying effect [21] was found in only one family carrying a pathogenic SPAST variation. In the present small material there was no correlation between age of onset and the presence of the p.Gly563Ala variant.…”

Section: Hspd1mentioning

confidence: 80%

“…These two suggested pathogenic mechanisms imply either haplo-insufficiency of the short isoform or dominant negative effect caused by increased ratio between the long isoform and the short isoform. Recently, another genetic modifier in HSPD1, the gene underlying SPG13, was reported to reduce age of onset in families with pathogenic variants in SPAST [21]. The functional mechanism of this modification is unknown.…”

Section: Introductionmentioning

confidence: 99%