The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis

Yang, Yi; Hentati, Afif; Deng, Han Xiang; Dabbagh, Omar; Sasaki, Tōru; Hirano, Minoru; Hung, Wu Yen; Ouahchi, Karim; Yan, Jianhua; Azim, Anser C.; Cole, Natalie; Gascon, Generoso G.; Yagmour, A.; Ben-Hamida, Mongi; Pericak‐Vance, Margaret A.; Hentati, Fayçal; Siddique, Teepu

doi:10.1038/ng1001-160

Cited by 659 publications

(441 citation statements)

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“…Mutations in SOD1 cause the classical form of ALS. Mutations in ALS2, which encodes the protein alsin, also give rise to a rare juvenile form of ALS [35,87], an infantile onset ascending hereditary spastic paralysis, and a form of complicated hereditary spastic paraplegia [11,16]. All mutations in ALS2, identified to date are missense mutations that result in unstable truncated alsin proteins implying that loss of alsin function induces the disease phenotypes [35,87].…”

Section: Alsinmentioning

confidence: 99%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3 % of children and young adults. MR has been consistently associated with changes in dendrites and dendritic spine structure. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to be the underlying cause of cognitive disabilities observed in MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore naturally attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. In support of this, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotropic lateral sclerosis (ALS). Here we will discuss Rho GTPase related genes and their signaling pathways involved in MR and ALS.

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Section: Alsinmentioning

confidence: 99%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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“…[20][21][22] ALS2 (Alsin) (OMIM gene *606352) is another prominent example of a gene implicated in pyramidal syndromes, with overlapping roles in other neurodegenerative conditions including amyotrophic lateral sclerosis. 23 Relatively little is known about the genetics of spinocerebellar degenerations in the Sudanese population. 24 In this article, we studied 25 families with progressive spastic neurodegenerative disorders in an effort to determine the genes underlying the disease.…”

Section: Introductionmentioning

confidence: 99%

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

et al. 2016

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Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSPrelated genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C4T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C4T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.

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“…Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) cause motor neuron degeneration through a gain of toxic property [2]. Recently, mutations in a second ALS-related gene (ALS2) were identified that cause a rare recessive form of juvenile onset ALS [5,9]. Previously, we and others have generated ALS2 knockout (ALS2 −/− ) mice that failed to display any obvious motor neuron degeneration [1,4].…”

Section: Introductionmentioning

confidence: 99%

Deficiency in the ALS2 gene does not affect the motor neuron degeneration in SOD1G93A transgenic mice

Lin

Shim

Cai

2007

Neurobiology of Aging

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Dysfunction of the ALS2 gene has been linked to one form of juvenile onset autosomal recessive amyotrophic lateral sclerosis (ALS). Previous in vitro studies suggest that over-expression of ALS2 protects cells from mutant Cu/Zn superoxide dismutase (SOD1)-induced cytotoxicity. To test whether ALS2 plays a protective role against mutant SOD1-mediated motor neuron degeneration in vivo, we examined the progression of motor neuron disease in SOD1 G93A mice on an ALS2 null background. Our data suggest that deficiency in the ALS2 gene does not affect the pathogenesis of SOD1 G93A mice.

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The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis

Cited by 659 publications

References 45 publications

Rho-linked genes and neurological disorders

Rho-linked genes and neurological disorders

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

Deficiency in the ALS2 gene does not affect the motor neuron degeneration in SOD1G93A transgenic mice

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