Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia

Shoukier, Moneef; Neesen, Jürgen; Sauter, Simone M.; Argyriou, Loukas; Doerwald, Nadine; Pantakani, DV Krishna; Mannan, Ashraf U.

doi:10.1038/ejhg.2008.147

Cited by 80 publications

(96 citation statements)

References 37 publications

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“…For climbing ability, a modified version of the assay described by Le Bourg and Lints (1992) was used. Flies were collected between 0 and 8 h after eclosion and assayed every 2 d from days 0 to 10.…”

Section: Methodsmentioning

confidence: 99%

“…loss of righting reflex assay (LORR) (Leal and Neckameyer, 2002) and the climbing assay (Le Bourg and Lints, 1992). LORR measures the time it takes adult flies to right themselves from a supine position, whereas the climbing assay measures whether a fly can vertically climb a set distance in a set amount of time.…”

Section: Expression Of Mutated M1 C448y In Transgenic Drosophila Affementioning

confidence: 99%

“…Genetic analyses have led to the view that haploinsufficiency is the molecular mechanism of the disease. In this view, axonal degeneration in HSP results from insufficient levels of spastin (Fonknechten et al, 2000;Lindsey et al, 2000). The haploinsufficiency model is buoyed by the fact that most of the Ͼ200 pathogenic mutations in SPG4 are nonsense or frameshift mutations, many of which would theoretically lead to mRNAs that undergo nonsensemediated decay (Bürger et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Severing regulates the number and mobility of MTs and the distribution of their plus ends (Baas et al, 2006) and may functionally link MT-severing to certain aspects of membrane trafficking (Allison et al, 2013). Studies on Drosophila and zebrafish indicate that experimental reductions of spastin can be harmful to axonal development (Sherwood et al, 2004;Trotta et al, 2004;Wood et al, 2006), but developmental abnormalities have not been observed in homozygous spastin knock-out mice (Tarrade et al, 2006;Kasher et al, 2009) or human patients with one inactive spastin allele. In addition, genetic analyses of HSP-SPG4 patients have not revealed a correlation between spastin levels and the severity of neurodegenerative symptoms (Yip et al, 2003, Shoukier et al, 2009, and there are even rare HSP patients with mutations in the SPG4 gene that are not function-blocking .…”

Section: Introductionmentioning

confidence: 99%

“…The haploinsufficiency model is buoyed by the fact that most of the Ͼ200 pathogenic mutations in SPG4 are nonsense or frameshift mutations, many of which would theoretically lead to mRNAs that undergo nonsensemediated decay (Bürger et al, 2000). Proponents of the model also point to the lack of detection of any truncated spastins in studies to date on human patients (Riano et al, 2009). However, there remain concerns about a model based exclusively on haploinsufficiency, especially because such a model offers no compelling explanation for why the disease is typically adult onset or why degeneration occurs mainly in the corticospinal tracts.…”

Section: Introductionmentioning

confidence: 99%

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Pathogenic Mutation of Spastin Has Gain-of-Function Effects on Microtubule Dynamics

et al. 2014

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Mutations to the SPG4 gene encoding the microtubule-severing protein spastin are the most common cause of hereditary spastic paraplegia. Haploinsufficiency, the prevalent model for the disease, cannot readily explain many of its key aspects, such as its adult onset or its specificity for the corticospinal tracts. Treatment strategies based solely on haploinsufficiency are therefore likely to fail. Toward developing effective therapies, here we investigated potential gain-of-function effects of mutant spastins. The full-length human spastin isoform called M1 or a slightly shorter isoform called M87, both carrying the same pathogenic mutation C448Y, were expressed in three model systems: primary rat cortical neurons, fibroblasts, and transgenic Drosophila. Although both isoforms had ill effects on motor function in transgenic flies and decreased neurite outgrowth from primary cortical neurons, mutant M1 was notably more toxic than mutant M87. The observed phenotypes did not result from dominant-negative effects of mutated spastins. Studies in cultured cells revealed that microtubules can be heavily decorated by mutant M1 but not mutant M87. Microtubule-bound mutant M1 decreased microtubule dynamics, whereas unbound M1 or M87 mutant spastins increased microtubule dynamics. The alterations in microtubule dynamics observed in the presence of mutated spastins are not consistent with haploinsufficiency and are better explained by a gain-offunction mechanism. Our results fortify a model wherein toxicity of mutant spastin proteins, especially mutant M1, contributes to axonal degeneration in the corticospinal tracts. Furthermore, our results provide details on the mechanism of the toxicity that may chart a course toward more effective treatment regimens.

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Section: Methodsmentioning

confidence: 99%

Section: Expression Of Mutated M1 C448y In Transgenic Drosophila Affementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pathogenic Mutation of Spastin Has Gain-of-Function Effects on Microtubule Dynamics

et al. 2014

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Autosomal Dominant Spastic Paraplegias

Loureiro¹,

Brandão²,

Ruano³

et al. 2013

JAMA Neurol

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Importance: Hereditary spastic paraplegias (HSPs) are a group of diseases caused by corticospinal tract degeneration. Mutations in 3 genes (SPG4, SPG3, and SPG31) are said to be the cause in half of the autosomal dominant HSPs (AD-HSPs). This study is a systematic review of families with HSP resulting from a population-based survey. Novel genotype-phenotype correlations were established. Objective: To describe the clinical, genetic, and epidemiological features of Portuguese AD-HSP families. Design: Retrospective medical record review. Setting: A population-based systematic survey of hereditary ataxias and spastic paraplegias conducted in Portugal from 1993 to 2004.

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Genetics of Motor Neuron Diseases

Chaudhary

Mishra

2023

Encyclopedia of Life Sciences

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Motor neuron diseases, also known as MNDs, are a group of extremely severe neurological conditions that, in most cases, result in death. These diseases are primarily characterised by the gradual degeneration and/or loss of motor neurons in the brainstem and spinal cord regions. Genetic mutations are one of the main triggers of MND pathogenesis, and researchers have identified more than 100 different genes in humans that have been altered. Previous studies have shown that many of the enzymatic transcriptional products produced by the defective or mutated genes that cause MNDs are involved in the dysregulation of several key intracellular and molecular pathways that are essential for proper motor neuron functioning. These include RNA transport and splicing, protein homeostasis, microglial cell activation, mitochondrial functions, axonal protein transport, protein folding and many more. Key Concepts Motor neuron disease is a fatal neurodegenerative condition that affects motor neurons in the central nervous system. Genetic factors play a major role in the initiation and progression of motor neuron disease. Over the past few years, hundreds of genes that play causative roles in motor neuron disorders have been discovered. Identifying novel genes or rare genetic variants involved in motor neuron disease pathophysiology is extremely vital. The use of various high‐throughput gene sequencing techniques has been shown to be an effective tool for discovering genes related to motor neuron diseases. Alterations in the expression of genes in motor neuron disease cause dysregulation of several intracellular pathways that are essential for healthy motoneuron functioning. The mechanism underlying the death of motor neurons is influenced by a number of different cellular and molecular processes. Toxic gain‐of‐function or loss‐of‐function of a specific protein causes abnormalities in synapse mechanisms, which leads to the degeneration or death of motor neurons. Even though the first case of motor neuron disease was documented more than a century ago, there is still no effective treatment or a viable cure available for the disease. At present, managing disease symptoms and providing palliative care are still the main goals of motor neuron disease therapy.

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Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia

Cited by 80 publications

References 37 publications

Pathogenic Mutation of Spastin Has Gain-of-Function Effects on Microtubule Dynamics

Pathogenic Mutation of Spastin Has Gain-of-Function Effects on Microtubule Dynamics

Autosomal Dominant Spastic Paraplegias

Genetics of Motor Neuron Diseases

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