* 300264
UBIQUILIN 2; UBQLN2
Alternative titles; symbols
PLIC2, MOUSE, HOMOLOG OF; PLIC2
CHAP1
HGNC Approved Gene Symbol: UBQLN2
Cytogenetic location: Xp11.21 Genomic coordinates (GRCh38): X:56,563,592-56,567,009 (from NCBI)
Gene-Phenotype Relationships
| Location | Phenotype | Phenotype MIM number |
Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| Xp11.21 | Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia | 300857 | X-linked dominant | 3 |
TEXT
Description
The UBQLN2 gene encodes ubiquilin-2, a member of the ubiquilin family of proteins that regulate the degradation of ubiquitinated proteins by the proteasome. Humans have 4 ubiquilin genes, each encoding a separate protein. Ubiquilins are characterized by the presence of an N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. The middle part of ubiquilins is highly variable. Ubiquilin-2 has a unique repeat region containing 12 PXX tandem repeats (summary by Deng et al., 2011).
Cloning and Expression
By performing independent yeast 2-hybrid screens, Kleijnen et al. (2000) isolated cDNAs encoding PLIC1 (UBQLN1; 605046) and PLIC2, homologs of the mouse Plics (proteins linking integrin-associated protein (IAP; 601028) and cytoskeleton) and the yeast Dsk2 protein. The predicted 624-amino acid PLIC2 protein, also called UBQLN2, shares 72% amino acid identity with PLIC1. Two motifs are conserved in the mammalian PLICs and yeast Dsk2, an N-terminal ubiquitin (191339)-like (UBL) domain and a C-terminal ubiquitin-associated (UBA) domain. Unlike ubiquitin, the UBL domain of the PLICs does not have a diglycine motif in its C terminus; the diglycine motif serves as a target site for cellular hydrolases that release ubiquitin from precursor fusion proteins. The absence of a GG sequence suggests that the UBL domain in the PLICs is an integral part of the open reading frame. The UBA domain is a loosely defined sequence motif present in multiple enzyme classes of the ubiquitination machinery. The most notable difference between the mammalian PLICs is the presence of a collagen-like motif in PLIC2 that is absent in PLIC1 and yeast Dsk2. This domain is most homologous to the collagen-like oncoprotein of Herpesvirus saimiri, STP-C488, which is implicated in intracellular signaling via the RAS-RAF pathway (see 190020). The collagen-like domain of PLIC2 contains 8 PXGP motifs that are susceptible to cleavage by collagenase in vitro. Kleijnen et al. (2000) showed that the human PLICs physically associate with both proteasomes and ubiquitin ligases in large complexes. Overexpression of PLICs interfered with the in vivo degradation of 2 unrelated ubiquitin-dependent proteasome substrates, p53 (191170) and I-kappa-B-alpha (NFKBIA; 164008), but not a ubiquitin-independent substrate. These findings raised the possibility that the PLICs, and possibly related ubiquitin-like family members, may functionally link the ubiquitination machinery to the proteasome to affect in vivo protein degradation.
By screening a human lung 2-hybrid cDNA library using a pGBT9-STCH (601100) plasmid as bait, Kaye et al. (2000) isolated a cDNA encoding UBQLN2, which they termed CHAP1/DSK2. Mutation analysis determined that the C-terminal Sti1-like repeat sequence, but neither the N-terminal UBL domain nor the C-terminal UBA domain, is required for binding of UBQLN2 to the ATPase domain of STCH.
Gene Structure
The UBQLN2 gene is intronless (Deng et al., 2011).
Mapping
By radiation hybrid analysis, Kaye and Shows (2000) mapped the UBQLN2 gene to chromosome Xp11.23-p11.1, a location linked to a number of neuropsychiatric disorders.
Gene Function
The ubiquitin-like domain of the ubiquilins binds to subunits in the proteasome and the ubiquitin-associated domain binds to the polyubiquitin chains that are typically conjugated onto proteins marked for degradation by the proteasome (summary by Deng et al., 2011).
By yeast 2-hybrid screening of a human brain cDNA library, Gilpin et al. (2015) found that the glycine-rich C-terminal ends of HNRNPA1 (164017), HNRNPA3 (605372), and HNRNPU (602869) interacted with the central domain of human UBQLN2. Protein interaction and coimmunoprecipitation assays confirmed binding between UBQLN2 and HNRNPA1 and HNRNPU. Knockdown of mouse Ubqln2 in NSC-34 motor neurons destabilized Hnrnpa1, increasing its turnover. All 5 ALS15 (300857)-associated mutations within a Pxx repeat in the central domain of UBQLN2 reduced its interaction with HNRNPA1. Similarly, an ALS20 (615423)-associated mutation in HNRNPA1 reduced its interaction with UBQLN2.
Molecular Genetics
Deng et al. (2011) identified 5 different mutations in ubiquilin-2 as causative of a familial form of ALS that is X-linked but 90% penetrant in females (ALS15; 300857). Each mutation involved proline residues in the PXX repeat region that is unique to UBQLN2. Functional analysis showed that these proline substitutions led to an impairment of protein degradation.
In affected members of a 5-generation family with a progressive neurodegenerative disorder comprising movement abnormalities and frontotemporal dementia, originally reported by DeMyer et al. (1964), Fahed et al. (2014) identified a heterozygous missense mutation in the UBQLN2 gene (P497L; 300264.0006). Functional studies of the variant were not performed.
Gilpin et al. (2015) found that all 5 ALS15-associated mutations (300264.0001-300264.0005) in the Pxx repeat region of UBQLN2 reduced interaction of UBQLN2 with HNRNPA1.
ALLELIC VARIANTS 6 Selected Examples):
.0001 AMYOTROPHIC LATERAL SCLEROSIS 15 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
In a 5-generation pedigree segregating apparently autosomal dominant ALS but without any male-to-male transmission (ALS15; 300857), Deng et al. (2011) identified a C-to-A transversion at nucleotide 1490 of the UBQLN2 gene, resulting in a pro-to-his substitution at codon 497 (P497H) of ubiquilin-2. This mutation segregated with the disorder in all affected family members. Two females were obligate carriers; 1 had not manifested at the time of her death at age 72, and the other was asymptomatic at age 71. One member of this family manifested ALS with dementia. This mutation was not present in 928 ethnically matched control samples representing 1,332 X chromosomes.
.0002 AMYOTROPHIC LATERAL SCLEROSIS 15 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
In a 3-generation family with apparently autosomal dominant ALS but without male-to-male transmission (ALS15; 300857), Deng et al. (2011) identified a C-to-T transition at nucleotide 1489 of the UBQLN2 gene, resulting in a pro-to-ser substitution at codon 497 (P497S) of ubiquilin-2. This mutation was not identified in 928 control samples. Half of the patients in this family had ALS with dementia.
.0003 AMYOTROPHIC LATERAL SCLEROSIS 15 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
In a 3-generation pedigree segregating apparently autosomal dominant ALS but with no male-to-male transmission (ALS15; 300857), Deng et al. (2011) identified a C-to-A transversion at nucleotide 1516 of the UBQLN2 gene, resulting in a pro-to-thr substitution at codon 506 (P506T) of ubiquilin-2. In this family there were individuals with isolated ALS as well as ALS with dementia. There was also 1 obligate carrier, aged 50 and asymptomatic. This mutation was not identified in 928 ethnically matched control samples.
.0004 AMYOTROPHIC LATERAL SCLEROSIS 15 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
In a family in which 2 sisters had ALS (ALS15; 300857), Deng et al. (2011) found that both had a C-to-T transition at nucleotide 1525 of the UBQLN2 gene, resulting in a pro-to-ser substitution at codon 509 (P509S) of ubiquilin-2. This mutation was not observed in 928 ethnically matched control samples.
.0005 AMYOTROPHIC LATERAL SCLEROSIS 15 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
Deng et al. (2011) identified 2 cousins with ALS (ALS15; 300857) who shared a C-to-T transition at nucleotide 1573 of the UBQLN2 gene, resulting in a pro-to-ser substitution at codon 525 (P525S) of ubiquilin-2. This mutation was not observed in 928 ethnically matched control samples. The cousins, male and female, had isolated ALS. The mothers of the cousins were sisters and obligate carriers; 1 died at 94 years of age asymptomatic, and the other other died at 78 years asymptomatic.
.0006 AMYOTROPHIC LATERAL SCLEROSIS 15 WITH FRONTOTEMPORAL DEMENTIA
In affected members of a 5-generation family with a neurodegenerative phenotype consistent with ALS15 with frontotemporal dementia (300857), originally reported by DeMyer et al. (1964), Fahed et al. (2014) identified a c.1490C-T transition in the UBQLN2 gene, resulting in a pro497-to-leu (P497L) substitution at a highly conserved residue within or upstream to a PXX repeat region. The mutation, which was found by exome sequencing, segregated with the disorder in the family and was not present in the 1000 Genomes Project or Exome Sequencing Project databases. Functional studies of the variant were not performed, but pathogenic mutations at this residue have been described in other families (P497H, 300264.0001 and P497S, 300264.0002). Most patients presented in the first 3 decades of life with progressive motor abnormalities, including abnormal movements and spastic paralysis, and frontotemporal dementia; males showed earlier onset than females. There was evidence of incomplete penetrance, as 1 female mutation carrier was well until age 63 years when she presented with typical ALS without dementia.
REFERENCES
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DeMyer, W., Harter, D. H., Zeman, W. Familial spasticity, hyperkinesia and dementia: clinicopathologic observations and comments on the nosology of Hallervorden-Spatz disease. Acta Neuropath. 4: 28-45, 1964.
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Deng, H.-X., Chen, W., Hong, S.-T., Boycott, K. M., Gorrie, G. H., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., and 11 others. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477: 211-215, 2011. [PubMed: 21857683] [Full Text: https://dx.doi.org/10.1038/nature10353]
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Fahed, A. C., McDonough, B., Gouvion, C. M., Newell, K. L., Dure, L. S., Bebin, M., Bick, A. G., Seidman, J. G., Harter, D. H., Seidman, C. E. UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration. Ann. Neurol. 75: 793-798, 2014. [PubMed: 24771548] [Full Text: https://doi.org/10.1002/ana.24164]
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Gilpin, K. M., Chang, L., Monteiro, M. J. ALS-linked mutations in ubiquilin-2 or hnRNPA1 reduce interaction between ubiquilin-2 and hnRNPA1. Hum. Molec. Genet. 24: 2565-2577, 2015. [PubMed: 25616961] [Full Text: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddv020]
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Kaye, F. J., Modi, S., Ivanovska, I., Koonin, E. V., Thress, K., Kubo, A., Kornbluth, S., Rose, M. D. A family of ubiquitin-like proteins binds the ATPase domain of Hsp70-like Stch. FEBS Lett. 467: 348-352, 2000. [PubMed: 10675567] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0014-5793(00)01135-2]
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Kaye, F. J., Shows, T. B. Assignment of ubiquilin 2 (UBQLN2) to human chromosome xp11.23-p11.1 by GeneBridge radiation hybrids. Cytogenet. Cell Genet. 89: 116-117, 2000. [PubMed: 10894951] [Full Text: https://dx.doi.org/10.1159/000015588]
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Kleijnen, M. F., Shih, A. H., Zhou, P., Kumar, S., Soccio, R. E., Kedersha, N. L., Gill, G., Howley, P. M. The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Molec. Cell 6: 409-419, 2000. [PubMed: 10983987] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S1097-2765(00)00040-X]
Cassandra L. Kniffin - updated : 10/29/2014
Ada Hamosh - updated : 9/21/2011
Paul J. Converse - updated : 9/26/2000
ckniffin : 9/3/2015
mgross : 7/24/2015
mgross : 7/21/2015
mcolton : 7/17/2015
carol : 2/4/2015
carol : 11/11/2014
carol : 11/10/2014
mcolton : 10/31/2014
ckniffin : 10/29/2014
alopez : 9/22/2011
terry : 9/21/2011
terry : 9/9/2010
wwang : 8/17/2010
carol : 5/12/2004
mgross : 9/26/2000
mgross : 9/14/2000