Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees  in northeast England

McDermott, Christopher J.; Dayaratne, R. K.; Tomkins, Janine; Lusher, Meryl E.; Lindsey, John H.; Johnson, Margaret; Casari, Giorgio; Turnbull, D. M.; Bushby, Kate; Shaw, Pamela J.

doi:10.1212/wnl.56.4.467

Cited by 88 publications

(84 citation statements)

References 17 publications

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“…Peripheral neuropathy, optic atrophy, and slight muscular involvement have been reported in a subset of patients (7,12). To test for the presence of these complicated clinical features, we analyzed the optic nerves, sciatic nerves, and skeletal muscles of paraplegin-deficient and control animals at different ages.…”

Section: Paraplegin-deficient Mice Develop Retrograde Degeneration Ofmentioning

confidence: 99%

“…Paraplegin localizes to mitochondria, and in some cases muscle biopsies from severely affected patients bearing paraplegin mutations showed signs of mitochondrial function impairment, such as ragged-red fibers and cytochrome c oxidase-deficient fibers (7,12). Recently, a mutation in mitochondrial heat shock protein 60 has been identified in a family with pure autosomal-dominant HSP (13), suggesting that some forms of HSP result from impairment of mitochondrial protein quality control.…”

Section: Introductionmentioning

confidence: 99%

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Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport

Ferreirinha¹,

Quattrini²,

Pirozzi³

et al. 2004

J. Clin. Invest.

128

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Section: Paraplegin-deficient Mice Develop Retrograde Degeneration Ofmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport

Ferreirinha¹,

Quattrini²,

Pirozzi³

et al. 2004

J. Clin. Invest.

128

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“…Mutations in the SPG7 gene (MIM 602783) cause an autosomal recessive (AR) form of HSP [Arnoldi et al, 2008;Brugman et al, 2008;Casari et al, 1998;Elleuch et al, 2006;McDermott et al, 2001;Tzoulis et al, 2008;Warnecke et al, 2007;Wilkinson et al, 2004]. The SPG7 gene codes for paraplegin, which contains an M41 metallopeptidase domain and an ATPase domain characteristic of the AAA family of ATPases [Langer, 2000].…”

Section: Introductionmentioning

confidence: 99%

Functional evaluation of paraplegin mutations by a yeast complementation assay

et al. 2010

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An autosomal recessive form of hereditary spastic paraplegia (AR-HSP) is primarily caused by mutations in the SPG7 gene, which codes for paraplegin, a subunit of the hetero-oligomeric m-AAA protease in mitochondria. In the current study, sequencing of the SPG7 gene in the genomic DNA of 25 unrelated HSP individuals/families led to the identification of two HSP patients with compound heterozygous mutations (p.G349S/p.W583C and p.A510V/p.N739KfsX741) in the coding sequence of the SPG7 gene. We used a yeast complementation assay to evaluate the functional consequence of novel SPG7 sequence variants detected in the HSP patients. We assessed the proteolytic activity of hetero-oligomeric m-AAA proteases composed of paraplegin variant(s) and proteolytically inactive forms of AFG3L2 (AFG3L2 E575Q or AFG3L2 K354A ) upon expression in m-AAA protease-deficient yeast cells. We demonstrate that the newly identified paraplegin variants perturb the proteolytic function of hetero-oligomeric m-AAA protease. Moreover, commonly occurring silent polymorphisms such as p.T503A and p.R688Q could be distinguished from mutations (p.G349S, p.W583C, p.A510V, and p.N739KfsX741) in our HSP cohort. The yeast complementation assay thus can serve as a reliable system to distinguish a pathogenic mutation from a silent polymorphism for any novel SPG7 sequence variant, which will facilitate the interpretation of genetic data for SPG7.

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“…Mutations in SPG7 were initially reported in three families, two with isolated spasticity and one with a complex phenotype (91), characterized by age of onset ranging from 10 to 45 years (92)(93)(94)(95), cerebellar involvement with/without mild cerebellar atrophy observed on MRI scans (91,93,94,96,97), optic neuropathy (91,92), ptosis (94,95) and supranuclear palsy (94). Optic neuropathy usually presents as mild or subclinical visual impairment, revealed only by OCT. SPG7-related DOA, on the other hand, is characterized by progressive visual loss starting the first decade of life, with final visual acuity of 1/10-3/10 in the second decade (89).…”

Section: Spg7mentioning

confidence: 99%

“…Among them, strong evidence has been provided regarding the pathogenic role of p.Ala510Val variant, which leads to disturbed proteolytic function of the heterooligomeric m-AAA protease (92,93,(97)(98)(99). On the other hand, Asp411Ala mutation, the first mutation segregating with isolated autosomal dominant optic neuropathy, is located in the AAA domain of the protein, downstream of the Walker B motif (which with the upstream Walker A motif are implicated in the fixation and hydrolysis of ATP) and causes impaired proteolytic activity (89).…”

Section: Spg7mentioning

confidence: 99%

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Bagli

Zikou

Agnantis

et al. 2017

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Abstract. Inherited optic neuropathies are a genetically diverse group of disorders mainly characterized by visual loss and optic atrophy. Since the first recognition of Leber's hereditary optic neuropathy, several genetic defects altering primary mitochondrial respiration have been proposed to contribute to the development of syndromic and nonsyndromic optic neuropathies. Moreover, the genomics and imaging revolution in the past decade has increased diagnostic efficiency and accuracy, allowing recognition of a link between mitochondrial dynamics machinery and a broad range of inherited neurodegenerative diseases involving the optic nerve. Mutations of novel genes modifying mainly the balance between mitochondrial fusion and fission have been shown to lead to overlapping clinical phenotypes ranging from isolated optic atrophy to severe, sometimes lethal multisystem disorders, and are reviewed herein. Given the particular vulnerability of retinal ganglion cells to mitochondrial dysfunction, the accessibility of the eye as a part of the central nervous system and improvements in technical imaging concerning assessment of the retinal nerve fiber layer, optic nerve evaluation becomes critical -even in asymptomatic patients -for correct diagnosis, understanding and early treatment of these complex and enigmatic clinical entities.Mitochondria represent a tubular and branched membrane system playing a fundamental role in several cellular processes required for the development and maintenance of an organism, such as metabolism, apoptosis, ion buffering and autophagy (1-3). They reveal a high degree of interconnectivity and plasticity, mainly dictated by metabolic status and developmental stage (4) and, therefore, a constant state of mitochondrial network flux is fundamental. This dynamic state is achieved through mitochondrial dynamics, a complex machinery of highly conserved mechanisms, including mitochondrial fusion, fission, transport, interorganellar communication and mitochondrial quality control (i.e. mitophagy), tuned to a variety of signals and stimuli (5-7), and well-orchestrated by specific intracellular proteins.The morphology and intracellular distribution of mitochondria vary significantly between tissues and cell types, being enriched in areas of increased metabolic demand, such as neurons, especially the presynaptic and postsynaptic terminals (8). Accordingly, it is not surprising that the pathogenic mechanism of various neurodegenerative diseases is established through an underlying deficiency of mitochondrial energy metabolism (9). However, in recent years it has been shown that impairment of mitochondrial dynamics also leads to synaptic dysfunction, dendritic and axonal degeneration and consequently to neurodegeneration (10,11). In this respect, restoration of mitochondrial function has become, for some time now, the priority target of novel neuroprotective strategies (12).Mitochondrial membrane dynamics, and more specifically fission and fusion, are indispensable for mitochondrial distribution and hom...

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Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees in northeast England

Cited by 88 publications

References 17 publications

Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport

Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport

Functional evaluation of paraplegin mutations by a yeast complementation assay

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

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