Functional evaluation of paraplegin mutations by a yeast complementation assay

Bonn, Florian; Pantakani, Krishna; Shoukier, Moneef; Langer, Thomas; Mannan, Ashraf U.

doi:10.1002/humu.21226

Cited by 37 publications

(54 citation statements)

References 24 publications

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“…It was also found to be the most common SPG7 variant in several other populations. 9,15,16,25 Whereas it was first thought to be a benign variant, its pathogenicity was later demonstrated 15,22 and its presence in our FC spastic ataxia cohort supports this claim. In addition, this variant was present at a frequency slightly above 1% in our in-house exome database.…”

Section: Discussionsupporting

confidence: 72%

“…This is significantly higher than public databases (1000 Genomes, EVS and ExAc), but is comparable to what has been reported in the literature for British, Spanish, Italian and German populations. 9,10,15,22 A threshold of one percent is frequently used for the filtering of recessive variants. However, 'not so rare' variants have been identified as causing recessive diseases and this should be taken into account when searching for disease variants altering protein function.…”

Section: Discussionmentioning

confidence: 99%

“…In parallel, we also identified variants in SPG7 in subject 22 using a Sanger sequencing HSP panel. This included five missense variants that were previously reported to affect the protein function, 5,7,10,15,22 and two novel variants (Table 1). In fact, five families (eight individuals) carried the novel splice site variant c.988-1G4A described above, making it the second most common variant in our cohort.…”

Section: Exome Sequencingmentioning

confidence: 99%

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SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

et al. 2015

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Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In Quebec, a significant number of patients affected with cerebellar ataxia and spasticity remain without a molecular diagnosis. We performed wholeexome sequencing in three French Canadian (FC) patients affected with spastic ataxia and uncovered compound heterozygous variants in SPG7 in all three. Sanger sequencing of SPG7 exons and exon/intron boundaries was used to screen additional patients. In total, we identified recessive variants in SPG7 in 22 FC patients belonging to 12 families (38.7% of the families screened), including two novel variants. The p.(Ala510Val) variant was the most common in our cohort. Cerebellar features, including ataxia, were more pronounced than spasticity in this cohort. These results strongly suggest that variants affecting the function of SPG7 are the fourth most common form of recessive ataxia in FC patients. Thus, we propose that SPG7 mutations explain a significant proportion of FC spastic ataxia cases and that this gene should be considered in unresolved patients. INTRODUCTIONHereditary cerebellar ataxias and hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous and often overlapping neurological disorders. HSPs are characterized by a predominant progressive spasticity and weakness in the lower limbs due to degeneration of the corticospinal tracts, 1 whereas the main feature of cerebellar ataxias is progressive cerebellar degeneration leading to impaired balance, gait and speech. 2 Both HSP and hereditary ataxias can be associated with other neurological and non-neurological features, resulting in complex phenotypes with frequent intra-and inter-familial variability. Significantly, cerebellar ataxias are very often associated with pyramidal involvement leading to 450% of recessive ataxias manifesting as spastic ataxias. 3 Because of the individual rarity and genetic heterogeneity of these conditions, their molecular diagnosis remains challenging and time-consuming.Mutations in the gene SPG7 were the first identified genetic cause of autosomal recessive HSP in 1998 (MIM602783). 4 Since then, a significant number of causative mutations were found in several HSP cohorts from different populations. 5-14 SPG7 can be characterized by a pure or complex HSP phenotype. Increasingly, reports documented that cerebellar ataxia and cerebellar atrophy on magnetic resonance imaging (MRI) are the most frequent additional features in complex SPG7 cases. 6,7,9,12,15 In a study of a large Dutch cohort, cerebellar ataxia was found in 57% of cases and it was even the

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Exome Sequencingmentioning

confidence: 99%

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SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

et al. 2015

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“…Direct sequencing of the corresponding exons and screening of the remaining SPG7 coding sequence in these patients revealed deleterious SPG7 mutations or deletions in six out of seven cases (Table 1, Patients 5-10); a synonymous polymorphism was identified in the seventh patient. In three out of the six positive patients, a pathogenic heterozygous mutation was associated with the heterozygous c.1529C4T/p.Ala510Val variant, previously described as a polymorphism and recently recognized as a hypomorphic and possibly pathogenic variant (Bonn et al, 2010).…”

Section: Genetic Analysesmentioning

confidence: 99%

Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

Klebe¹,

Depienne²,

Gerber³

et al. 2013

Basal Ganglia

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Mutations in the spastic paraplegia 7 (SPG7) gene encoding paraplegin are responsible for autosomal recessive hereditary spasticity. We screened 135 unrelated index cases, selected in five different settings: SPG7-positive patients detected during SPG31 analysis using SPG31/SPG7 multiplex ligation-dependent probe amplification (n = 7); previously reported ambiguous SPG7 cases (n = 5); patients carefully selected on the basis of their phenotype (spasticity of the lower limbs with cerebellar signs and/or cerebellar atrophy on magnetic resonance imaging/computer tomography scan and/or optic neuropathy and without other signs) (n = 24); patients with hereditary spastic paraparesis referred consecutively from attending neurologists and the national reference centre in a diagnostic setting (n = 98); and the index case of a four-generation family with autosomal dominant optic neuropathy but no spasticity linked to the SPG7 locus. We identified two SPG7 mutations in 23/134 spastic patients, 21% of the patients selected according to phenotype but only 8% of those referred directly. Our results confirm the pathogenicity of Ala510Val, which was the most frequent mutation in our series (65%) and segregated at the homozygous state with spastic paraparesis in a large family with autosomal recessive inheritance. All SPG7-positive patients tested had optic neuropathy or abnormalities revealed by optical coherence tomography, indicating that abnormalities in optical coherence tomography could be a clinical biomarker for SPG7 testing. In addition, the presence of late-onset very slowly progressive spastic gait (median age 39 years, range 18-52 years) associated with cerebellar ataxia (39%) or cerebellar atrophy (47%) constitute, with abnormal optical coherence tomography, key features pointing towards SPG7-testing. Interestingly, three relatives of patients with heterozygote SPG7 mutations had cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs, suggesting that SPG7 mutations at the heterozygous state might predispose to late-onset neurodegenerative disorders, mimicking autosomal dominant inheritance. Finally, a novel missense SPG7 mutation at the heterozygous state (Asp411Ala) was identified as the cause of autosomal dominant optic neuropathy in a large family, indicating that some SPG7 mutations can occasionally be dominantly inherited and be an uncommon cause of isolated optic neuropathy. Altogether, these results emphasize the clinical variability associated with SPG7 mutations, ranging from optic neuropathy to spastic paraplegia, and support the view that SPG7 screening should be carried out in both conditions.

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“…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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Functional evaluation of paraplegin mutations by a yeast complementation assay

Cited by 37 publications

References 24 publications

SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

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