UBQLN2

protein-coding

ubiquilin 2, the group of Ubiquilin family

Gene summary

This gene encodes an ubiquitin-like protein (ubiquilin) that shares high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain a N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and ubiquitin ligases; and thus, are thought to functionally link the ubiquitination machinery to the proteasome to affect in vivo protein degradation. This ubiquilin has also been shown to bind the ATPase domain of the Hsp70-like Stch protein. [provided by RefSeq, Oct 2009]

MANE transcript

NM_013444.4

Inheritance

XL, AD

ClinVar variants

P:9U:148B:77

Top phenotype

Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chrX:56,563,627-56,567,868

External References & Databases

Ensembl (ENSG00000188021)

Transcript & Mutation Effects

hg38 • Region Span ~4.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyotrophic lateral sclerosis type 15STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010459

Submitter: Labcorp Genetics (formerly Invitae)

amyotrophic lateral sclerosis type 15DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010459

Submitter: ClinGen

UBQLN2 was first reported in relation to X-linked dominant amyotrophic lateral sclerosis 15 (ALS) in 2011 (Deng HX, et al., 2011, PMID: 21857683). UBQLN2 encodes ubiquilin 2, which is mainly involved in protein homeostasis, directing misfolded or redundant proteins towards the proteasome. ALS is 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. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. At least 29 missense variants have been reported in relation to ALS. Variants in this gene have been reported in at least 30 probands in 13 publications (PMIDs: 21857683, 23138764, 22717235, 24771548, 28716533, 23312802, 22892309, 22560112, 31475037, 23582661, 24684794, 25179229, 25681989), and segregated with disease in at least 21 additional family member. Experimentally, this gene-disease relationship is supported by its role in the ubiquitin-dependent protein catabolic process (PMID: 15147878), which is altered in cells expressing variants (PMID: 26075709). Additionally, its role in autophagy is also altered in patient cells (PMID: 28716533) and it interacts in stress granules with additional ALS-implicated genes FUS and TIA1 (PMID: 30442662). Further support is provided by several animal models (drosophila, rat, and mouse) including at least two knock-in mouse models (PMID: 27834214), which recapitulate features of ALS. In summary UBQLN2 is definitively associated with X-linked dominant amyotrophic lateral sclerosis 15. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen ALS GCEP on 04/13/2021 (SOPv8).

amyotrophic lateral sclerosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

amyotrophic lateral sclerosis type 15STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010459

Submitter: Genomics England PanelApp

amyotrophic lateral sclerosis type 15MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010459

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Amyotrophic lateral sclerosis 15, with or without frontotemporal dementiaXL

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: 21857683; 24771548

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UBQLN2 variants in ClinVar

6 Conditions Cataloged

Amyotrophic lateral sclerosis type 15Total: 181

not providedTotal: 58

not specifiedTotal: 32

UBQLN2-related disorderTotal: 22

Vascular dementiaTotal: 1

Amyotrophic lateral sclerosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013444.4. 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			20 clinvar	57 clinvar	8 clinvar	85
missense	3 clinvar	6 clinvar	127 clinvar	11 clinvar	1 clinvar	148
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	3	6	148	68	9	234

Highest pathogenic variant AF is 0.000010936831

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_013444.4	RefSeq	NP_038472.2	1	MANE Select
ENST00000338222.7	Ensembl	ENSP00000345195.5	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein processing in endoplasmic reticulum - Homo sapiens (human)
Vesicle-mediated transport
Membrane Trafficking
Clathrin-mediated endocytosis
Cargo recognition for clathrin-mediated endocytosis

Biological Process

autophagy
regulation of macroautophagy
ubiquitin-dependent ERAD pathway
negative regulation of clathrin-dependent endocytosis
positive regulation of ER-associated ubiquitin-dependent protein catabolic process

Molecular Function

protein binding

Cellular Component

nucleus
cytoplasm
autophagosome
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000338222
Coding exons: 1
Length: 3418
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.50	172	237	0.726	0.0000159	4112
Missense (PolyPhen)		30	53.899	0.5566		1067
Synonymous	-1.51	116	97.0	1.20	0.00000675	1312
Loss of Function	2.73	1	10.6	0.0943	6.79e-7	156

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin- proteasome system (UPS), autophagy and the endoplasmic reticulum- associated protein degradation (ERAD) pathway. Mediates the proteasomal targeting of misfolded or accumulated proteins for degradation by binding (via UBA domain) to their polyubiquitin chains and by interacting (via ubiquitin-like domain) with the subunits of the proteasome (PubMed:10983987). Plays a role in the ERAD pathway via its interaction with ER-localized proteins FAF2/UBXD8 and HERPUD1 and may form a link between the polyubiquitinated ERAD substrates and the proteasome (PubMed:24215460, PubMed:18307982). Involved in the regulation of macroautophagy and autophagosome formation; required for maturation of autophagy-related protein LC3 from the cytosolic form LC3-I to the membrane-bound form LC3-II and may assist in the maturation of autophagosomes to autolysosomes by mediating autophagosome-lysosome fusion (PubMed:19148225, PubMed:20529957). Negatively regulates the endocytosis of GPCR receptors: AVPR2 and ADRB2, by specifically reducing the rate at which receptor- arrestin complexes concentrate in clathrin-coated pits (CCPs) (PubMed:18199683). {ECO:0000269|PubMed:10983987, ECO:0000269|PubMed:18199683, ECO:0000269|PubMed:18307982, ECO:0000269|PubMed:19148225, ECO:0000269|PubMed:20529957, ECO:0000269|PubMed:24215460}.;
Disease: DISEASE: Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (ALS15) [MIM:300857]: 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. Patients with ALS15 may develop frontotemporal dementia. {ECO:0000269|PubMed:21857683, ECO:0000269|PubMed:22560112, ECO:0000269|PubMed:22717235, ECO:0000269|PubMed:22892309, ECO:0000269|PubMed:24215460, ECO:0000269|PubMed:25616961}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.131
RVIS EVS: -0.36
RVIS percentile EVS: 28.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.741

Gene Damage Prediction

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