Alternative titles; symbols
HGNC Approved Gene Symbol: UBQLN1
Cytogenetic location: 9q21.32 Genomic coordinates (GRCh38) : 9:83,659,968-83,707,958 (from NCBI)
Using a yeast 2-hybrid system to screen an adult rat lung cDNA library, Ozaki et al. (1997) isolated a cDNA, which they termed DA41, encoding a cellular protein that can associate with DAN (600613). Expression of DAN had been found to be significantly reduced in rat fibroblast 3Y1 cells transformed with mouse sarcoma virus and in rodent fibroblasts transformed with a variety of oncogenes. Ozaki et al. (1997) determined that the interaction between DAN and DA41 is mediated through the N-terminal domain and a cystine knot region of DAN. Expression of DA41 is regulated in a cell cycle-dependent manner.
By screening a human lung cDNA library with a rat DA41 cDNA as a probe, Hanaoka et al. (2000) isolated the human DA41 homolog. Human DA41 encodes a 589-amino acid protein with a predicted molecular mass of 62.4 kD. The protein shows 86% amino acid sequence identity with the rat protein, indicating the evolutionarily conserved structure and function of DA41. DA41 was expressed ubiquitously in adult human tissues, with relatively higher levels in pituitary gland, adrenal gland, kidney, thymus, and placenta.
By performing independent yeast 2-hybrid screens, Kleijnen et al. (2000) isolated cDNAs encoding PLIC1 and PLIC2 (UBQLN2; 300264), homologs of the mouse Plics (proteins linking integrin-associated protein (IAP; 601028) and cytoskeleton) and the yeast Dsk2 protein. PLIC1, also called UBQLN1, shares 72% amino acid identity with PLIC2. 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.
Neurodegenerative Alzheimer disease (AD; 104300) is associated with extracellular depositions of proteolytic fragments of amyloid precursor protein (APP; 104760). Using Western blot analysis, Stieren et al. (2011) found that UBQLN1 expression was reduced in postmortem AD brain at all stages of AD development except the earliest preclinical stage. UBQLN1 downregulation preceded significant neuronal cell loss in preclinical samples. Yeast 2-hybrid analysis of a rat brain cDNA library showed that human UBQLN1 interacted with the APP intracellular domain. UBQLN1 also immunoprecipitated with APP in cotransfected HeLa cells. The amount of UBQLN1 that coprecipitated with APP increased following crosslinking, suggesting that the complex was transient. Coexpression of UBQLN1 with APP reduced the content of amyloid deposits in APP-overexpressing rat PC12 cells and reduced production of pathogenic amyloid-beta peptides produced by APP-expressing HeLa cells. In vitro, UBQLN1 significantly protected a test protein against heat denaturation. Stieren et al. (2011) concluded that UBQLN1 functions as a chaperone for APP and that diminished UBQLN1 levels in AD may contribute to pathogenesis.
Gonzalez-Perez et al. (2012) noted that UBQLN1 directly interacts with TDP43 (605078) in yeast and in human cells in vitro.
Sweetser et al. (2005) determined that the UBQLN1 gene contains 11 exons.
By fluorescence in situ hybridization, Hanaoka et al. (2000) mapped the DA41 gene to chromosome 9q21.2-q21.3, a position overlapping a candidate tumor suppressor locus for bladder cancer (see 109800).
Bird (2005) reviewed genetic factors in Alzheimer disease (AD; see 104300) and the interrelationship with nongenetic factors. They commented that UBQLN1 is an intriguing candidate gene because of its potential role in the proteasome degradation of proteins and its interaction with PSEN1 and PSEN2.
Bertram et al. (2005) estimated that mutations in the 4 genes that have been related to Alzheimer disease--APP (104760), PSEN1 (104311), PSEN2 (600759), and APOE4 (107741)--may account for less than half the genetic variance in Alzheimer disease, and that possibly up to 7 additional Alzheimer disease genes remained to be identified. They focused on the fact that the UBQLN1 gene is one of these candidate genes by virtue of its location at a well-established linkage peak for AD on chromosome 9q22. Bertram et al. (2005) evaluated 19 single-nucleotide polymorphisms (SNPs) in 3 genes within the 9q22 region in 437 multiplex families with Alzheimer disease from an NIMH sample. They found a positive association between Alzheimer disease and various SNPs in UBQLN1 (UBQ-8i, rs2791001, {dbSNP 2780995}). They confirmed these associations in an independent sample of families. The risk-conferring haplotype in both samples was defined by the single intronic SNP located downstream of exon 8. The risk allele was associated with a dose-dependent increase in an alternatively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain samples of patients with Alzheimer disease. Bertram et al. (2005) interpreted the findings as indicating that genetic variants in UBQLN1 on 9q22 increase the risk of Alzheimer disease, possibly by influencing alternative splicing of this gene in the brain.
Slifer et al. (2005) found no association between the risk of Alzheimer disease and a genetic variant of the UBQ-8i SNP (rs12344615) but did find significant association between this risk allele and an older age of onset in a recessive disease model in their case-control data set.
Smemo et al. (2006) found no association between the UBQ-8i SNP and Alzheimer disease among a group of 1,544 patients with late-onset AD. There was also no association between AD and 6 other polymorphisms in the UBQLN1 gene.
Kamboh et al. (2006) studied the association of UBQLN1 gene variation with Alzheimer disease and examined the association of UBQLN1 SNPs with quantitative measures of Alzheimer disease progression, namely age at onset, disease duration, and Mini Mental Status Examination scores. They examined the association of 3 SNPs in the gene (intron 6 A/C, intron 8 T/C, and intron 9 A/G), all of which are in significant linkage disequilibrium (p less than 0.0001), in up to 978 late-onset Alzheimer disease patients and 808 controls. Modestly significant associations were observed in the single-site regression analysis, but 3-site haplotype analysis revealed significant associations (p less than 0.0001). One common haplotype, called H4 (ACG for introns 6, 8, and 9, respectively), was associated with Alzheimer disease risk, and one less common haplotype, called H5 (CCA for introns 6, 8, and 9, respectively), was associated with protection. The adjusted odds ratios with potentially 1 or 2 copies of risk haplotype H4 were 1.5 (95% CI, 0.99-2.26; p = 0.054) and 3.66 (95% CI, 1.43-9.39; p = 0.007), respectively, and the odds ratio for haplotype H5 carriers was 0.31 (95% CI, 0.10-0.95; p = 0.0398). Kamboh et al. (2006) suggested that genetic variation in the UBQLN1 gene has a modest effect on risk, age at onset, and disease duration of Alzheimer disease and that the presence of additional putative functional variants either in UBQLN1 or nearby genes exist.
Gonzalez-Perez et al. (2012) did not find an association between variation in the UBQLN1 gene and amyotrophic lateral sclerosis (see, e.g., 105400) in about 200 patients with familial or sporadic ALS. Additional testing for specific SNPs and possible coding variants of UBQLN1 in other patient cohorts comprising over 1,000 patients also did not show an association with ALS.
Associations Pending Confirmation
For discussion of a possible association between intellectual disability and variation in the UBQLN1 gene, see 605046.0001.
For discussion of a possible association between Brown-Vialetto-Van Laere syndrome (see e.g., BVVLS1, 211530) and variation in the UBQLN1 gene, see 605046.0002.
Ganguly et al. (2008) showed that Drosophila Ubqn, the homolog of UBQLN1, binds to Psen1 (104311) and antagonizes Psen1 function in vivo. Loss of Ubqn suppressed phenotypes that resulted from loss of Psen1 function in vivo. Overexpression of Ubqn in the eye resulted in adult-onset, age-dependent retinal degeneration, which could be suppressed by Psen1 overexpression and enhanced by expression of a dominant-negative version of Psen1. Expression of a human AD-associated UBQLN1 variant led to more severe degeneration than expression of wildtype UBQLN1. The findings identified Ubqn as a regulator of Psen1, supported a role for UBQLN1 in AD pathogenesis, and suggested that the expression of a human AD-associated variant can cause neurodegeneration independent of amyloid production.
This variant is classified as a variant of unknown significance because its contribution to intellectual disability has not been confirmed.
In 2 sibs (BAB4810 and BAB4807), born of consanguineous parents (family HOU1936), with intellectual disability, Karaca et al. (2015) identified a homozygous 1-bp deletion (c.377delA, NM_053067) in the UBQLN1 gene, predicted to resulted in a frameshift (Asn126Metfs) and complete loss of function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but Karaca et al. (2015) noted that the UBQLN1 gene is involved in proteasome degradation. Clinical details were limited, but the sister had dolichocephaly, low-set ears, and early loss of teeth, whereas the brother had dilated lateral ventricles and Arnold-Chiari malformation on brain imaging. The family was part of a cohort of 128 mostly consanguineous families with neurogenetic disorders, often including brain malformations, that underwent whole-exome sequencing.
This variant is classified as a variant of unknown significance because its contribution to Brown-Vialetto-Van Laere syndrome (see e.g., BVVLS1, 211530) has not been confirmed.
In an Italian woman with a motor neuron disease consistent with Brown-Vialetto-Van Laere syndrome, Gonzalez-Perez et al. (2012) identified a heterozygous c.162G-T transversion in exon 1 of the UBQLN1 gene, resulting in a glu54-to-asp (E54D) substitution at a highly conserved residue in the UBL domain. In vitro functional expression studies in cells showed that the E54D variant resulted in increased mislocalization of TDP43 (605078) from the nucleus to the cytoplasm compared to controls. E54D also coimmunostained with TDP43 in cytoplasmic aggregates, whereas wildtype UBQLN1 did not. The findings suggested that the E54D variant may inhibit ubiquitin degradation. The variant was identified thorough direct screening of the UBQLN1 gene in about 200 patients with sporadic or familial amyotrophic lateral sclerosis (see, e.g., ALS, 105400). The E54D variant was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 1,378 controls. It was also not found among 1,474 patients with sporadic ALS, suggesting that it is a rare contributor, if at all, to motor neuron disease. The patient had no family history of a similar disorder.
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Bird, T. D. Genetic factors in Alzheimer's disease. New Eng. J. Med. 352: 862-864, 2005. [PubMed: 15745976] [Full Text: https://doi.org/10.1056/NEJMp058027]
Ganguly, A., Feldman, R. M. R., Guo, M. Ubiquilin antagonizes presenilin and promotes neurodegeneration in Drosophila. Hum. Molec. Genet. 17: 293-302, 2008. [PubMed: 17947293] [Full Text: https://doi.org/10.1093/hmg/ddm305]
Gonzalez-Perez, P., Lu, Y., Chian, R.-J., Sapp, P. C., Tanzi, R. E., Bertram, L., McKenna-Yasek, D., Gao, F.-B., Brown, R. H., Jr. Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS. Neurobiol. Dis. 48: 391-398, 2012. [PubMed: 22766032] [Full Text: https://doi.org/10.1016/j.nbd.2012.06.018]
Hanaoka, E., Ozaki, T., Ohira, M., Nakamura, Y., Suzuki, M., Takahashi, E., Moriya, H., Nakagawara, A., Sakiyama, S. Molecular cloning and expression analysis of the human DA41 gene and its mapping to chromosome 9q21.2-q21.3. J. Hum. Genet. 45: 188-191, 2000. [PubMed: 10807547] [Full Text: https://doi.org/10.1007/s100380050209]
Kamboh, M. I., Minster, R. L., Feingold, E., DeKosky, S. T. Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures. Molec. Psychiat. 11: 273-279, 2006. [PubMed: 16302009] [Full Text: https://doi.org/10.1038/sj.mp.4001775]
Karaca, E., Harel, T., Pehlivan, D., Jhangiani, S. N., Gambin, T., Akdemir, Z. C., Gonzaga-Jauregui, C., Erdin, S., Bayram, Y., Campbell, I. M., Hunter, J. V., Atik, M. M., and 52 others. Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease. Neuron 88: 499-513, 2015. [PubMed: 26539891] [Full Text: https://doi.org/10.1016/j.neuron.2015.09.048]
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://doi.org/10.1016/s1097-2765(00)00040-x]
Ozaki, T., Hishiki, T., Toyama, Y., Yuasa, S., Nakagawara, A., Sakiyama, S. Identification of a new cellular protein that can interact specifically with DAN. DNA Cell Biol. 16: 985-991, 1997. [PubMed: 9303440] [Full Text: https://doi.org/10.1089/dna.1997.16.985]
Slifer, M. A., Martin, E. R., Haines, J. L., Pericak-Vance, M. A. The ubiquilin 1 gene and Alzheimer's disease. (Letter) New Eng. J. Med. 352: 2752-2753, 2005. [PubMed: 15987928] [Full Text: https://doi.org/10.1056/NEJM200506303522618]
Smemo, S., Nowotny, P., Hinrichs, A. L., Kauwe, J. S. K., Cherny, S., Erickson, K., Myers, A. J., Kaleem, M., Marlowe, L., Gibson, A. M., Hollingworth, P., O'Donovan, M. C., and 11 others. Ubiquilin 1 polymorphisms are not associated with late-onset Alzheimer's disease. Ann. Neurol. 59: 21-26, 2006. [PubMed: 16278862] [Full Text: https://doi.org/10.1002/ana.20673]
Stieren, E. S., El Ayadi, A., Xiao, Y., Siller, E., Landsverk, M. L., Oberhauser, A. F., Barral, J. M., Boehning, D. Ubiquilin-1 is a molecular chaperone for the amyloid precursor protein. J. Biol. Chem. 286: 35689-35698, 2011. [PubMed: 21852239] [Full Text: https://doi.org/10.1074/jbc.M111.243147]
Sweetser, D. A., Peniket, A. J., Haaland, C., Blomberg, A. A., Zhang, Y., Zaidi, S. T., Dayyani, F., Zhao, Z., Heerema, N. A., Boultwood, J., Dewald, G. W., Paietta, E., Slovak, M. L., Willman, C. L., Wainscoat, J. S., Bernstein, I. D., Daly, S. B. Delineation of the minimal commonly deleted segment and identification of candidate tumor-suppressor genes in del(9q) acute myeloid leukemia. Genes Chromosomes Cancer 44: 279-291, 2005. [PubMed: 16015647] [Full Text: https://doi.org/10.1002/gcc.20236]