A novel
            <i>ALS2</i>
            splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family

Mintchev, Nikolay; Zamba‐Papanicolaou, Eleni; Kleopa, Kleopas A.; Christodoulou, Kyproula

doi:10.1212/01.wnl.0000338530.77394.60

Cited by 27 publications

(23 citation statements)

References 26 publications

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“…Alsin mutations are known to cause not only ALS, but also juvenile forms of PLS and infantile‐onset ascending hereditary spastic paraplegia. Mutations of other genes linked with ALS like C9ORF72 have been found in PLS as well.…”

Section: Discussionmentioning

confidence: 99%

The concept and diagnostic criteria of primary lateral sclerosis

et al. 2016

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Our data show that PLS as a disease entity is still not well enough defined and that there are different concepts about its clinical presentation. We believe that further prospective longitudinal studies are needed in order to refine diagnostic criteria to reflect current clinical practice. Furthermore, neuropathological and neuroimaging approaches might help to arrange PLS in the MND spectrum and its classification.

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Section: Discussionmentioning

confidence: 99%

The concept and diagnostic criteria of primary lateral sclerosis

et al. 2016

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“…These disorders are characterized by ascending degeneration of UMN with or without LMN involvement. A total of 19 independent ALS2 mutations from 17 families have been reported [4], [5], [6], [10], [11], [12], [13], [14]. They are predicted to result in either premature termination of translation or substitution of an evolutionarily conserved amino acid for the ALS2 -coded protein, ALS2 or alsin, leading to loss of its function.…”

Section: Introductionmentioning

confidence: 99%

Loss of ALS2/Alsin Exacerbates Motor Dysfunction in a SOD1H46R-Expressing Mouse ALS Model by Disturbing Endolysosomal Trafficking

et al. 2010

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BackgroundALS2/alsin is a guanine nucleotide exchange factor for the small GTPase Rab5 and involved in macropinocytosis-associated endosome fusion and trafficking, and neurite outgrowth. ALS2 deficiency accounts for a number of juvenile recessive motor neuron diseases (MNDs). Recently, it has been shown that ALS2 plays a role in neuroprotection against MND-associated pathological insults, such as toxicity induced by mutant Cu/Zn superoxide dismutase (SOD1). However, molecular mechanisms underlying the relationship between ALS2-associated cellular function and its neuroprotective role remain unclear.Methodology/Principal FindingsTo address this issue, we investigated the molecular and pathological basis for the phenotypic modification of mutant SOD1-expressing mice by ALS2 loss. Genetic ablation of Als2 in SOD1H46R, but not SOD1G93A, transgenic mice aggravated the mutant SOD1-associated disease symptoms such as body weight loss and motor dysfunction, leading to the earlier death. Light and electron microscopic examinations revealed the presence of degenerating and/or swollen spinal axons accumulating granular aggregates and autophagosome-like vesicles in early- and even pre-symptomatic SOD1H46R mice. Further, enhanced accumulation of insoluble high molecular weight SOD1, poly-ubiquitinated proteins, and macroautophagy-associated proteins such as polyubiquitin-binding protein p62/SQSTM1 and a lipidated form of light chain 3 (LC3-II), emerged in ALS2-deficient SOD1H46R mice. Intriguingly, ALS2 was colocalized with LC3 and p62, and partly with SOD1 on autophagosome/endosome hybrid compartments, and loss of ALS2 significantly lowered the lysosome-dependent clearance of LC3 and p62 in cultured cells.Conclusions/SignificanceBased on these observations, although molecular basis for the distinctive susceptibilities to ALS2 loss in different mutant SOD1-expressing ALS models is still elusive, disturbance of the endolysosomal system by ALS2 loss may exacerbate the SOD1H46R-mediated neurotoxicity by accelerating the accumulation of immature vesicles and misfolded proteins in the spinal cord. We propose that ALS2 is implicated in endolysosomal trafficking through the fusion between endosomes and autophagosomes, thereby regulating endolysosomal protein degradation in vivo.

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“…4 ALS2 mutations are distributed widely across the entire coding sequence and mostly result in loss of protein function. 4–6 …”

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confidence: 99%

ALS2 mutations

et al. 2014

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Objective:To determine the genetic etiology in 2 consanguineous families who presented a novel phenotype of autosomal recessive juvenile amyotrophic lateral sclerosis associated with generalized dystonia.Methods:A combination of homozygosity mapping and whole-exome sequencing in the first family and Sanger sequencing of candidate genes in the second family were used.Results:Both families were found to have homozygous loss-of-function mutations in the amyotrophic lateral sclerosis 2 (juvenile) (ALS2) gene.Conclusions:We report generalized dystonia and cerebellar signs in association with ALS2-related disease. We suggest that the ALS2 gene should be screened for mutations in patients who present with a similar phenotype.

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A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family

Cited by 27 publications

References 26 publications

The concept and diagnostic criteria of primary lateral sclerosis

The concept and diagnostic criteria of primary lateral sclerosis

Loss of ALS2/Alsin Exacerbates Motor Dysfunction in a SOD1H46R-Expressing Mouse ALS Model by Disturbing Endolysosomal Trafficking

ALS2 mutations

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