Alternative titles; symbols
HGNC Approved Gene Symbol: ALS2
SNOMEDCT: 703543005, 717964007;
Cytogenetic location: 2q33.1 Genomic coordinates (GRCh38) : 2:201,700,267-201,780,933 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.1 | Amyotrophic lateral sclerosis 2, juvenile | 205100 | Autosomal recessive | 3 |
| Primary lateral sclerosis, juvenile | 606353 | Autosomal recessive | 3 | |
| Spastic paralysis, infantile onset ascending | 607225 | Autosomal recessive | 3 |
Alsin, which is encoded by the ALS2 gene, is a member of the guanine nucleotide exchange factors for the small GTPase RAB5 (179512) and plays a role in intracellular endosomal trafficking (summary by Hadano et al., 2006).
By positional cloning, Yang et al. (2001) and Hadano et al. (2001) isolated a gene found to be mutant in families with juvenile amyotrophic lateral sclerosis-2 (ALS2; 205100) or juvenile primary lateral sclerosis (PLSJ; 606353). The coding sequence gives rise to a deduced 184-kD 1,657-residue long form of the protein, and alternative splicing after exon 4 yields a 396-residue short form. Yang et al. (2001) and Hadano et al. (2001) both determined that the deduced ALS2 protein contains several guanine-nucleotide exchange factor domains, consistent with a function in cell signaling. By Northern blot analysis, Yang et al. (2001) detected 2 mRNA bands of 2.3 and 6 kb, whereas Hadano et al. (2001) reported mRNA bands of 2.6 and 6.5 kb. The ALS2 gene is expressed in various tissues and cells, including neurons throughout the brain and spinal cord. It was found to be identical to KIAA1563, identified by Nagase et al. (2000).
Yang et al. (2001) and Hadano et al. (2001) independently determined that the ALS2 gene comprises 34 exons in a genomic region of 83 kb.
Otomo et al. (2003) showed that the ALS2 protein specifically binds to small GTPase RAB5 (179512) and functions as a guanine nucleotide exchange factor (GEF) for RAB5. Ectopically expressed ALS2 localized with RAB5 and early endosome antigen-1 (EEA1; 605070) onto early endosomal compartments and stimulated the enlargement of endosomes in cultured cortical neurons. The C terminus of ALS2 carrying a VPS9 domain mediated not only the activation of RAB5 via a guanine-nucleotide exchanging reaction but also the endosomal localization of ALS2, whereas the N-terminal region containing the RCC1 (179710)-like domain acted suppressive in its membranous localization. The DH/PH domain in the middle portion of ALS2 enhanced the VPS9 domain-mediated endosome fusions. Otomo et al. (2003) hypothesized that a perturbation of endosomal dynamics caused by loss of the ALS2 functional domain that confers RAB5 GEF activity might underlie neuronal dysfunction and degeneration in a number of motor neuron diseases.
Kanekura et al. (2004) found that the long 1,657-residue isoform of ALS2 bound to mutant SOD1 (147450) via the RhoGEF domain and protected mouse motor neurons from toxicity induced by mutant SOD1. In contrast, the short 396-residue isoform of ALS2 and truncating pathogenic ALS2 mutations did not protect mouse neurons from mutant SOD1 toxicity. The long isoform of ALS2 did not bind to wildtype SOD1, but the short ALS2 isoform did bind to wildtype SOD1. Further studies indicated that the C-terminal region of ALS2 prevents the long isoform from binding to wildtype SOD1. The long isoform of ALS2 did not protect neurons against other non-ALS insults, such as mutant PS1 (104311), SNCA (163890), or APP (104760). The findings suggested a functional link between 2 ALS-related genes.
Among 3 families reported by Yang et al. (2001) and Hadano et al. (2001), 1 had a 1-bp deletion in exon 3 (606352.0001) of the ALS2 gene, which resulted in the more severe juvenile ALS phenotype, whereas 2 had 2-bp deletions in exons 9 and 5 of the ALS2 gene, (606352.0002; 606352.0004), respectively, which resulted in the milder juvenile primary lateral sclerosis phenotype. The authors suggested that the milder PLSJ phenotype may have occurred because of an intact short protein or some preservation of function of the mutated longer protein. The truncating nature of the mutations and the recessive pattern of inheritance suggested that motor neuron degeneration is the result of a loss of function.
Eymard-Pierre et al. (2002) identified homozygous mutations in the ALS2 gene (606352.0005-606352.0008) in affected members of 4 of 10 families with infantile-onset ascending spastic paralysis (IAHSP; 607225). All the mutations led to a truncated alsin protein. The authors noted that ALS2 mutations are responsible for a primitive, retrograde degeneration of the upper motor neurons of the pyramidal tracts, resulting in a clinical continuum from infantile (IAHSP) to juvenile forms with (ALS2) or without (PLSJ) lower motor neuron involvement.
Al-Chalabi et al. (2003) stated that 7 mutations in the ALS2 gene had been reported in association with various forms of ALS. However, Al-Chalabi et al. (2003) found no significant association between variants in the ALS2 gene and sporadic ALS (see 105400). The authors concluded that variants of the ALS2 gene are not a common cause of a predominantly early-onset, upper motor neuron disease phenotype of sporadic ALS, nor are they associated with a more typical phenotype.
Among 201 patients with familial, sporadic, or early-onset ALS, Hand et al. (2003) found no pathogenic mutations in the ALS2 gene, suggesting that mutations in the ALS2 gene are not a common cause of ALS.
Devon et al. (2006) found that Als2-null mice were born in the expected mendelian ratio and were indistinguishable from their wildtype littermates in size, appearance, and overall behavior. Als2 deficiency did not affect fertility or fecundity. However, Als2-deficient mice exhibited significant but subtle neuropathologic changes. Cytosol from brains of Als2-null mice showed marked diminution of Rab5-dependent endosome fusion activity. Primary neurons from Als2-null mice showed a disturbance in endosomal transport of Igf1 receptor (IGF1R; 147370) and Bdnf receptor (NTRK2; 600456), whereas neuronal viability and endocytosis of transferrin (TF; 190000) and dextran seemed unaltered. There was a significant decrease in the size of cortical motor neurons, and Als2-null mice were mildly hypoactive.
Yamanaka et al. (2006) found that Als2-null mice showed progressive axonal degeneration in the lateral spinal cord that was also prominent in mutant SOD1 (147450) mice, a model for human ALS. Lower motor neurons were preserved in Als2-null mice, a finding that is distinct from classic ALS, which shows both upper and lower motor neuron involvement. Phenotypically, Als2-null mice showed slowed movement without muscle weakness, consistent with upper motor neuron defects that lead to spasticity in humans.
Hadano et al. (2006) found that Als2-null mice observed through 21 months of age demonstrated no obvious developmental, reproductive or motor abnormalities. However, immunohistochemical and electrophysiologic analyses showed an age-dependent, slowly progressive loss of cerebellar Purkinje cells, a disturbance of spinal motor neurons associated with astrocytosis and microglial cell activation, and a progressive loss of motor axons, indicating a subclinical dysfunction of the motor system in Als2-null mice. Quantitative EGF-uptake analysis showed significantly smaller-sized EGF-positive endosomes in Als2-null fibroblasts, suggesting an alteration of intracellular endosome/vesicle trafficking. Overall, however, the mice did not show a profound defect in motor performance, as seen in humans.
Otomo et al. (2008) found that hippocampal neurons from Als2-null mice had a delay in axon outgrowth and decreased macropinocytosis. Als2 colocalized with F-actin in vesicles and in membrane ruffles at the edge of growth cones in sprouting neurites. Axon outgrowth was delayed, but did occur, in Als2-null cells, and the survival rate of the cells was not affected. Otomo et al. (2008) suggested that ALS2 may act as a modulator in neuronal differentiation or development through regulation of membrane dynamics.
Jacquier et al. (2009) demonstrated that alsin-depleted murine spinal motor neurons could be rescued from defective survival and axon growth by cocultured astrocytes. The astrocytic rescue was mediated by an unidentified soluble protective factor rather than by cellular contact. Cortical neurons were intrinsically as vulnerable to alsin depletion as spinal motor neurons, but could not be rescued by cocultured astrocytes.
In affected members of a Tunisian family with juvenile amyotrophic lateral sclerosis-2 (ALS2; 205100) reported by Ben Hamida et al. (1990) and Hentati et al. (1992, 1994), Yang et al. (2001) and Hadano et al. (2001) identified a homozygous 1-bp deletion (138delA) in exon 3 of the ALS2 gene, resulting in a frameshift and a premature stop codon 4 codons after the deletion site. The 1-bp deletion occurred in codon 46 for alanine and the premature stop was at codon 50. The deletion affected both the long and short forms of the protein. The mutation was not identified in 533 control individuals (Hadano et al., 2001).
Hadano (2002) pointed out that this mutation, which Hadano et al. (2001) identified as 261delA, should be referred to as 138delA.
In 3 affected members of a consanguineous Saudi Arabian family with juvenile primary lateral sclerosis (PLSJ; 606353), Yang et al. (2001) identified a homozygous 2-bp deletion (1867delCT) in exon 9 of the ALS2 gene. This deletion led to a frameshift and premature stop codon 23 codons after the deletion site. A deletion occurred in codon 623 for leucine and the premature stop was created at codon 646.
In a Kuwaiti family reported by Lerman-Sagie et al. (1996) in which affected members showed early development of progressive spasticity but no evidence of denervation in the first 2 decades of life, Hadano et al. (2001) identified a homozygous 2-bp deletion (1425delAG) in exon 5 of the ALS2 gene. Shaw (2001) classified this family as having primary lateral sclerosis (PLSJ; 606353) because of the lack of evidence of denervation.
In a personal communication, Hadano (2002) pointed out that the mutation identified by Hadano et al. (2001) as 1548delAG should be referred to as 1425delAG.
In 3 members of a family (family 362) with infantile-onset ascending spastic paralysis (IAHSP; 607225), Eymard-Pierre et al. (2002) found a homozygous 1-bp deletion (3742delA) in exon 22 in the long ALS2 transcript, causing a frameshift and a stop codon at met1206.
In a patient (family 419) with infantile-onset ascending spastic paralysis (IAHSP; 607225), Eymard-Pierre et al. (2002) found a homozygous 10-bp deletion at nucleotide 1471 in exon 6 of the long ALS2 transcript. The deletion led to a frameshift and a premature stop codon at amino acid 493. Genomic DNA analysis with primers amplifying exon 6 and the corresponding splice site regions demonstrated a homozygous point mutation (G to T) in the consensus CAG acceptor splice site of exon 6. Both parents and 1 unaffected sib were heterozygous for the mutation.
In a patient (family 283) with infantile-onset ascending spastic paralysis (IAHSP; 607225), Eymard-Pierre et al. (2002) found a homozygous 2-bp deletion at nucleotide 2660 (2660delAT) in exon 13 of the long ALS2 transcript. The deletion led to a frameshift at asn845 and a premature stop codon 12 codons after the deletion site at amino acid 858. The parents for heterozygous for the mutation, and an unaffected brother was homozygous for the normal allele.
In a patient (family 278) with infantile-onset ascending spastic paralysis (IAHSP; 607225), Eymard-Pierre et al. (2002) found a homozygous 2-bp deletion at nucleotide 1130 (1130delAT) in exon 4 of both the short and the long ALS2 transcripts. The deletion led to a frameshift and a premature translation termination at amino acid 335. Both parents and an unaffected sib were heterozygous for the mutation.
In a large consanguineous Pakistani family with infantile-onset complicated spastic paraparesis (IAHSP; 607225), Gros-Louis et al. (2003) identified a 1-bp deletion (4844delT) in exon 32 of the ALS2 gene. The proband presented with gait disturbance and hyperreflexia at 18 months and was anarthric and wheelchair-bound by age 12 years. Family history indicated that the disease slowly progressed to tetraplegia and death by the fourth decade, with relatively preserved intellect. The mutation cosegregated with the disease in the family and was absent in 155 control individuals.
In 2 sisters, born of first-cousin Buchari Jewish parents, with infantile-onset ascending spastic paraplegia (IAHSP; 607225) with bulbar involvement, Devon et al. (2003) found homozygosity for a 3115C-T transition in the ALS2 gene, predicted to result in a stop codon in place of an arginine at amino acid 998 (R998X). This sequence change would lead to premature termination of the protein with presumed loss of function. Both parents were heterozygous for the mutation. The clinical phenotype of the sisters was practically identical. Development was normal until 12 to 14 months of age, when signs of spasticity were noted. By 2 years of age, both sisters showed spasticity in the arms. By 3 years of age, 1 sister developed supranuclear bulbar palsy, which included involuntary laughing, hyperactive gag and jaw jerk reflexes, and progressive dysarthria. At 6 years of age, the other sister had pseudobulbar palsy with a weak and dysarthric voice that was hard to comprehend.
In a Turkish man, born of consanguineous parents, with juvenile amyotrophic lateral sclerosis-2 (ALS2; 205100), Kress et al. (2005) identified a homozygous 1-bp deletion (553delA) in exon 4 of the ALS2 gene, resulting in a frameshift and premature termination of the protein at residue 189. The mutation affects both the long and short forms of the protein. The patient had a severe disease course; onset occurred at age 2 years and he was wheelchair-bound by age 16. The patient's unaffected parents and 2 unaffected brothers were heterozygous for the mutation.
In 2 affected sisters with infantile-onset ascending spastic paralysis (IAHSP; 607225), born of consanguineous Turkish parents, Eymard-Pierre et al. (2006) identified a homozygous 669G-A transition in exon 4 of the ALS2 gene, resulting in a cys156-to-tyr (C156Y) substitution in a highly conserved residue in the RCC1-like domain. Immunoblot analysis showed absence of the ALS2 protein in patient lymphoblasts. Functional expression studies in HEK293 cells showed decreased stability of the mutant protein and loss of ALS2 activity.
In 3 affected members of a consanguineous Cypriot family with juvenile primary lateral sclerosis (PLSJ; 606353), Mintchev et al. (2009) identified a homozygous A-to-G transition in intron 17 of the ALS2 gene, resulting in the loss of exon 18 and premature termination. Onset was at age 2 years, with leg spasticity, bulbar paresis, and prominent saccadic gaze paresis. One patient became wheelchair-bound at age 50 years, the second never achieved ambulation, and the third remained ambulatory at age 16.
In 2 Dutch sibs, born of consanguineous parents, with infantile-onset ascending spastic paralysis (IAHSP; 607225), Verschuuren-Bemelmans et al. (2008) identified a homozygous 2143C-T transition in exon 10 of the ALS2 gene, resulting in a gln715-to-ter (Q715X) substitution, predicted to result in a truncated protein. The unaffected parents were each heterozygous for the mutation. The parents were descended from a common ancestor who lived during the 18th century in the province of Friesland, in the northern part of the Netherlands.
In 2 sibs, born of consanguineous Saudi parents, with infantile-onset ascending spastic paralysis (IAHSP; 607225), Wakil et al. (2014) identified a homozygous c.2761C-T transition in exon 15 of the ALS2 gene, resulting in an arg921-to-ter (R921X) substitution in the pleckstrin domain. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. It was not present in 184 Saudi controls. After normal early development, both patients developed progressive spastic paraplegia around the age of walking and became wheelchair-bound in mid-childhood. Other features included spastic anarthria and swallowing difficulties; cognition was normal.
In 2 sibs, born of consanguineous Bangladeshi parents, with juvenile amyotrophic lateral sclerosis-2 (ALS2; 205100), Sheerin et al. (2014) identified a homozygous c.2002G-T transversion in the ALS2 gene, resulting in a gly668-to-ter (G668X) substitution. The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Functional studies were not performed. In addition to ALS, both patients had dystonia, nystagmus, and microcephaly, and 1 had ataxia. Functional studies of the variant were not performed.
In 2 sibs, born of consanguineous Turkish parents, with juvenile amyotrophic lateral sclerosis-2 (ALS2; 205100), Sheerin et al. (2014) identified a homozygous 1-bp duplication (c.4573dupG) in the ALS2 gene, resulting in a frameshift and premature termination (Val1525fs). The mutation, which was found by candidate gene sequencing, segregated with the disorder in the family and was not present in the Exome Variant Server database. In addition to ALS, both patients had generalized dystonia. Functional studies of the variant were not performed.
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