ALS2

protein-coding

alsin Rho guanine nucleotide exchange factor ALS2, the group of Dbl family Rho GEFs|VPS9 domain containing

Gene summary

The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

Previous symbols:

ALS2CR6

MANE transcript

NM_020919.4

Inheritance

ClinVar variants

P:129U:469B:246

Top phenotype

Spastic paralysis, infantile onset ascending; Primary lateral sclerosis, juvenile; Amyotrophic lateral sclerosis 2

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr2:201,700,267-201,782,112

External References & Databases

Ensembl (ENSG00000003393)

Transcript & Mutation Effects

hg38 • Region Span ~81.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

juvenile primary lateral sclerosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011663

Submitter: Orphanet

juvenile primary lateral sclerosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011663

Submitter: Genomics England PanelApp

amyotrophic lateral sclerosis type 2, juvenileSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008780

Submitter: Genomics England PanelApp

ALS2-related motor neuron diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100227

Submitter: ClinGen

*ALS2* was first reported in relation to motor neuron disease in 2001 (Hadano S, et al., 2001, PMID: 11586298). From GeneReviews, Pathogenic variants in *ALS2* are responsible for a retrograde degeneration of the upper motor neurons of the pyramidal tracts, leading to phenotypes on a clinical continuum ranging from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile forms without lower motor neuron involvement (juvenile primary lateral sclerosis [JPLS]) or with lower motor neuron involvement (juvenile amyotrophic lateral sclerosis [JALS]), and as such have been lumped into a single disease entity for curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Thirteen variants have been curated in relation to motor neuron disease (including frameshift, nonsense, and splice variants as well as some missense), found in 12 probands in 5 publications (PMIDs: 11586298, 16240357, 23282280, 24562058, 33155358). Cosegregation of variants with disease was reported in at least 18 family members as well. Additional evidence is available in the literature but the maximum score for genetic evidence was reached. Experimentally, this gene-disease relationship is supported by its biochemical function; *ALS2* encodes Alsin, which regulates actin-based neurite outgrowth (PMID: 16049005) as a prominent guanine nucleotide exchange factor (GEF) for the small GTPase Rab5 (PMID: 12837691). The pathomechanism of *ALS2* mutations is considered to be loss of function, and likely involves unlinking or disturbing the connections between *ALS2* and Rab5, which reduces actin-based intracellular trafficking and glutamate signaling at synapses (Lai et al., 2009). The presence of both Rac1 and Rab5 GEF activities makes Alsin a unique dual exchange factor that may couple endocytosis (via Rab5 activation) to cytoskeletal modulation (via Rac1 activation). Several different lines of *ALS2* knockout (ALS2–/–) mice have been generated by independent groups (PMIDs: 16107644, 16321985, 16769894, 16802286, 16675207, 17855450). The loss of alsin does not have a drastic effect on the survival or function of motor neurons in mice. However, subtle deficits observed in the behavior and pathology of these mice have aided in the understanding of the relationship between alsin and motor neuron dysfunction. In summary, there is definitive evidence to support the gene-disease relationship of autosomal recessive *ALS2* related motor neuron disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

infantile-onset ascending hereditary spastic paralysisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011797

Submitter: Labcorp Genetics (formerly Invitae)

juvenile primary lateral sclerosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011663

Submitter: Labcorp Genetics (formerly Invitae)

juvenile amyotrophic lateral sclerosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017593

Submitter: Orphanet

infantile-onset ascending hereditary spastic paralysisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011797

Submitter: Orphanet

infantile-onset ascending hereditary spastic paralysisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011797

Submitter: Genomics England PanelApp

ALS2-related motor neuron diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100227

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spastic paralysis, infantile onset ascending; Primary lateral sclerosis, juvenile; Amyotrophic lateral sclerosis 2AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 2328408; 7920663; 8745388; 11586298; 11586297; 12145748; 12509863; 16718699; 18523452; 18810511; 19122027

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALS2 variants in ClinVar

21 Conditions Cataloged

Infantile-onset ascending hereditary spastic paralysisTotal: 797

not providedTotal: 235

Inborn genetic diseasesTotal: 147

ALS2-related disorderTotal: 105

Amyotrophic lateral sclerosis type 2, juvenileTotal: 104

not specifiedTotal: 64

Hereditary spastic paraplegiaTotal: 39

Juvenile primary lateral sclerosisTotal: 22

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020919.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			22 clinvar	212 clinvar	4 clinvar	238
missense	4 clinvar	12 clinvar	435 clinvar	30 clinvar		481
nonsense	24 clinvar	16 clinvar	5 clinvar			45
start loss						0
frameshift	25 clinvar	17 clinvar	2 clinvar			44
splice donor/acceptor (+/-2bp)	12 clinvar	19 clinvar	5 clinvar			36
Total	65	64	469	242	4	844

Highest pathogenic variant AF is 0.00003323266

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 81 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020919.4	RefSeq	NP_065970.2	33	MANE Select
ENST00000264276.11	Ensembl	ENSP00000264276.6	33	MANE Select
NM_001135745.2	RefSeq	NP_001129217.1	3	Standard
NM_001410975.1	RefSeq	NP_001397904.1	33	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
als2b	Danio rerio	Structure: motor neuron Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

als2b

Danio rerio

Structure: motor neuron

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human)
Amyotrophic lateral sclerosis (ALS)
Vesicle-mediated transport
Membrane Trafficking
Rab regulation of trafficking

Biological Process

behavioral fear response
in utero embryonic development
receptor recycling
response to oxidative stress
endosome organization

Molecular Function

guanyl-nucleotide exchange factor activity
protein binding
Rab guanyl-nucleotide exchange factor activity
Rab GTPase binding
Rac guanyl-nucleotide exchange factor activity

Cellular Component

ruffle
early endosome
centrosome
cytosol
postsynaptic density

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264276
Coding exons: 33
Length: 80636
Individuals with no LoFs: 124625
Homozygous LoFs: 0
Heterozygous LoFs: 177
Defined: 124802
p: 0.000709

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.90	713	870	0.819	0.0000459	10787
Missense (PolyPhen)		142	245.32	0.57885		3020
Synonymous	0.485	317	328	0.966	0.0000181	3249
Loss of Function	5.42	36	92.2	0.390	0.00000510	1069

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00098	0.00097	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00039	0.00039	rare
Finnish	0.0013	0.0013	notable
European (Non-Finnish)	0.00089	0.00088	rare
South Asian	0.00042	0.00036	rare
Other	0.00066	0.00066	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as a GTPase regulator. Controls survival and growth of spinal motoneurons (By similarity). {ECO:0000250}.;
Disease: DISEASE: Amyotrophic lateral sclerosis 2 (ALS2) [MIM:205100]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:11586298}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Juvenile primary lateral sclerosis (JPLS) [MIM:606353]: A neurodegenerative disorder which is closely related to but clinically distinct from amyotrophic lateral sclerosis. It is a progressive paralytic disorder which results from dysfunction of the upper motor neurons while the lower neurons are unaffected. {ECO:0000269|PubMed:11586297}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Infantile-onset ascending spastic paralysis (IAHSP) [MIM:607225]: Characterized by progressive spasticity and weakness of limbs. {ECO:0000269|PubMed:12145748}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.318
RVIS EVS: -1.46
RVIS percentile EVS: 3.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.873

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium