Alsin Related Disorders: Literature Review and Case Study with Novel Mutations

Flôr-de-Lima, Filipa; Sampaio, Mafalda; Nahavandi, Nahid; Fernandes, Susana; Leão, Miguel

doi:10.1155/2014/691515

Cited by 11 publications

(11 citation statements)

References 15 publications

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“…At least 22 of the reported ALS2 pathogenic variants have been associated with IAHSP and have been described in a total of 42 individuals. The majority of reported cases originate from the Middle East and Mediterranean countries [2][3][4][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Table 2 provides a summary of the mutations and clinical features of the previously reported IAHSP cases.…”

Section: Discussionmentioning

confidence: 99%

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant

et al. 2018

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Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course.

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Section: Discussionmentioning

confidence: 99%

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant

et al. 2018

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“…In neurons, these activities are important in multiple membrane-processing activities, not only in the Golgi and ER but also in neuronal devel-opment and remodeling, synaptic function, and neurotransmitter receptor trafficking. Individuals with loss-of-function mutations in alsin develop early-onset corticospinal tract and lower motor degeneration, which, unlike typical adult-onset ALS, is slowly progressive with survival measured in decades (Flor- de-Lima et al 2014).…”

Section: Juvenile-onset Als Genesmentioning

confidence: 99%

Genetics of Amyotrophic Lateral Sclerosis

Ghasemi

Brown

2017

Cold Spring Harb Perspect Med

189

132

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Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disorder of motor neurons that overlaps clinically with frontotemporal dementia (FTD). Investigations of the 10% of ALS cases that are transmitted as dominant traits have revealed numerous gene mutations and variants that either cause these disorders or influence their clinical phenotype. The evolving understanding of the genetic architecture of ALS has illuminated broad themes in the molecular pathophysiology of both familial and sporadic ALS and FTD. These central themes encompass disturbances of protein homeostasis, alterations in the biology of RNA binding proteins, and defects in cytoskeletal dynamics, as well as numerous downstream pathophysiological events. Together, these findings from ALS genetics provide new insight into therapies that target genetically distinct subsets of ALS and FTD.

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“…Recently, several missense or in-frame deletion mutations in the ALS2 gene, which are predicted to code for mutant proteins preserving the C-terminal Rab5 GEF domain (i.e. ALS2 G49R (13), ALS2 F65S (12), ALS2 S100I (14), ALS2 A120del (15), ALS2 C157Y (16), ALS2 P192L (18), ALS2 G540E (20), ALS2 A861_T904del (14), ALS2 S1116_T1170del (29), and ALS2 R1611W (15)), were identified ( Fig. S1).…”

mentioning

confidence: 99%

Altered oligomeric states in pathogenic ALS2 variants associated with juvenile motor neuron diseases cause loss of ALS2-mediated endosomal function

Sato

Otomo

Ueda

et al. 2018

Journal of Biological Chemistry

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Familial amyotrophic lateral sclerosis type 2 (ALS2) is a juvenile autosomal recessive motor neuron disease caused by the mutations in the gene. The gene product, ALS2/alsin, forms a homophilic oligomer and acts as a guanine nucleotide-exchange factor (GEF) for the small GTPase Rab5. This oligomerization is crucial for both Rab5 activation and ALS2-mediated endosome fusion and maturation in cells. Recently, we have shown that pathogenic missense ALS2 mutants retaining the Rab5 GEF activity fail to properly localize to endosomes via Rac1-stimulated macropinocytosis. However, the molecular mechanisms underlying dysregulated distribution of ALS2 variants remain poorly understood. Therefore, we sought to clarify the relationship between intracellular localization and oligomeric states of pathogenic ALS2 variants. Upon Rac family small GTPase 1 (Rac1) activation, all mutants tested moved from the cytosol to membrane ruffles but not to macropinosomes and/or endosomes. Furthermore, most WT ALS2 complexes were tetramers. Importantly, the sizes of an ALS2 complex carrying missense mutations in the N terminus of the regulator of chromosome condensation 1-like domain (RLD) or in-frame deletion in the pleckstrin homology domain were shifted toward higher molecular weight, whereas the C-terminal vacuolar protein sorting 9 (VPS9) domain missense mutant existed as a smaller dimeric or trimeric smaller form. Furthermore, mutagenesis analyses using the RLD protein structure in conjunction with a cycloheximide chase assay disclosed that these missense mutations led to a decrease in protein stability. Collectively, disorganized higher structures of ALS2 variants might explain their impaired endosomal localization and the stability, leading to loss of the ALS2 function.

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Alsin Related Disorders: Literature Review and Case Study with Novel Mutations

Cited by 11 publications

References 15 publications

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant

Genetics of Amyotrophic Lateral Sclerosis

Altered oligomeric states in pathogenic ALS2 variants associated with juvenile motor neuron diseases cause loss of ALS2-mediated endosomal function

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