Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33–q35

Hentati, Afif; Bejaoui, Khemissa; Pericak‐Vance, Margaret A.; Hentati, Fayçal; Speer, Marcy C.; Hung, Wu Yen; Figlewicz, Denise A.; Haines, Jonathan L.; Rimmler, Jacqueline; Hamida, Christiane Ben; Hamida, M. Ben; Brown, Robert H.; Siddique, Teepu

doi:10.1038/ng0794-425

Cited by 184 publications

(89 citation statements)

References 12 publications

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“…The second gene identified is mutated in a juvenile form of ALS, ALS2 (13,14). Mutations in this gene lead to a rare recessive form of ALS that presents early in life and progresses much more slowly than the classical form (6,15). Two small deletions in ALS2 were originally associated with the disease (13,14).…”

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Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor

Topp

Gray

Gerard

et al. 2004

Journal of Biological Chemistry

171

157

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ALS2 is the gene mutated in a recessive juvenile form of amyotrophic lateral sclerosis (ALS2). ALS2 encodes a large protein termed alsin, which contains a number of predicted cell signaling and protein trafficking sequence motifs. To gain insight into the overall function of alsin and to begin to evaluate its role in motor neuron maintenance, we examined the subcellular localization of alsin and the biochemical activities associated with its individual subdomains. We found that the Vps9p domain of alsin has Rab5 guanine nucleotide exchange activity. In addition, alsin interacted specifically with and acted as a guanine nucleotide exchange factor for Rac1. Immunofluorescence and fractionation experiments in both fibroblasts and neurons revealed that alsin is a cytosolic protein, with a significant portion associated with small, punctate membrane structures. Many of these membrane structures also contained Rab5 or Rac1. Upon overexpression of full-length alsin, the overexpressed material was largely cytosolic, indicating that the association with membrane structures could be saturated. We also found that alsin was present in membrane ruffles and lamellipodia. These data suggest that alsin is involved in membrane transport events, potentially linking endocytic processes and actin cytoskeleton remodeling.Amyotrophic lateral sclerosis (ALS) 1 is a heterogeneous neurological disorder characterized by progressive degeneration of motor neurons, usually causing death as a result of respiratory paralysis (1, 2). Although mostly sporadic in nature, a genetic link has been established in 5-10% of ALS cases (3). Chromosomal mapping studies have identified six independent loci associated with the familial forms of ALS (Refs. 4 -10; reviewed in Refs. 11 and 12). Molecular genetic analysis identified two genes that, when mutated, lead to ALS. The first discovered was the gene coding for Cu-Zn superoxide dismutase 1 (SOD1) (10). Initially, mutations in SOD1 were thought to result in defective free radical scavenger activity. However, it is now generally accepted that the alterations in SOD1 that lead to ALS are the result of an unknown, but toxic gain-of-function. The second gene identified is mutated in a juvenile form of ALS, ALS2 (13,14). Mutations in this gene lead to a rare recessive form of ALS that presents early in life and progresses much more slowly than the classical form (6, 15). Two small deletions in ALS2 were originally associated with the disease (13,14). Each is expected to severely truncate the predicted protein product of ALS2. In addition, mutations in ALS2 have recently been associated with two other neurodegenerative disorders, juvenile-onset primary lateral sclerosis (14) and infantile-onset hereditary spastic paralegia (16 -18). Like the original mutations identified, these mutations are predicted to generate prematurely truncated forms of the protein product.The protein encoded by ALS2, alsin, is predicted to contain numerous domains implicating roles in cell signaling, membrane localization, and protein...

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mentioning

confidence: 99%

Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor

Topp

Gray

Gerard

et al. 2004

Journal of Biological Chemistry

171

157

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“…FALS is usually inherited as autosomal dominant trait 3 though a few kindreds show autosomal recessive inheritance. 4 ' 5 Approximately 15% of all dominant FALS are caused by a defect in the cytosolic Cu/Zn superoxide dismutase gene (SODl) localized to human chromosome 21q22.1. 6,7 To date forty-five different missense mutations affecting 34 codons, one nonsense mutation, one deletion mutation causing a frameshift and two intronic mutation in intron 4 have been described in the SODl gene.…”

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Identification of Six Novel SOD1 Gene Mutations in Familial Amyotrophic Lateral Sclerosis

Boukaftane

Khoris

Moulard³

et al. 1998

Can. j. neurol. sci.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature death of motor neurons. In approximately 10% of the cases the disease is inherited as autosomal dominant trait (FALS). It has been found that mutations in the Cu/Zn superoxide dismutase gene (SODl) are responsible for approximately 15% of FALS kindreds. We screened affected individuals from 70 unrelated FALS kindreds and identified 10 mutations, 6 of which are novel. Surprisingly, we have found a mutation in exon 3, which includes most of the active site loop and Zn 2+ binding sites, a region where no previous SODl mutations have been found. Our data increase the number of different SODl mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protein. RESUME: Identification de six nouvelles mutations dans le gene SODl de patients atteints de laSclerose Laterale Amyotrophique. La Sclerose Laterale Amyotrophique (SLA) est une maladie neurodegenerative caracterisee par la mort prematuree des motoneurones. Dans 10% des cas, la SLA est herediataire et caracterisee par une transmission autosomique dominante (SLAF). II a ete prouve que des mutations dans le gene codant pour la Cu/Zn superoxyde dismutase (SODl) sont responsables de 15% des cas de SLAF. L'analyse des regions condantes du gene SODl de 70 patients nonapparentes atteints de SLAF nous a permis de decouvrir 10 mutations dont six sont nouvelles. Fait inatendu, nous avons trouve la premiere mutation dans l'exon 3 qui code pour la majeure partie du site actif et des sites de fixation du Zn 2+ . De plus, nous avons identife une deuxieme mutation recessive. Cette etude porte le nombre de mutations SODl differentes a 55 impliquant 37 codons, une fraction significative de cette proteine relativement petite constitute de 154 acides amines.

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“…ALS2 is an autosomal recessive form of juvenile ALS that was first reported in a large consanguineous Tunisian kindred and linkage analysis in this family associated locus 2q33-q35 to ALS (Hentati et al, 1994). This led to the discovery of causal mutations in the gene encoding ALSin (Hadano et al, 2001;Yang et al, 2001).…”

Section: Als2 (Alsin)mentioning

confidence: 99%