Alternative titles; symbols
HGNC Approved Gene Symbol: TRIM32
SNOMEDCT: 240064008, 43226001;
Cytogenetic location: 9q33.1 Genomic coordinates (GRCh38) : 9:116,687,305-116,701,299 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q33.1 | ?Bardet-Biedl syndrome 11 | 615988 | Autosomal recessive | 3 |
| Muscular dystrophy, limb-girdle, autosomal recessive 8 | 254110 | Autosomal recessive | 3 |
Members of the tripartite motif (TRIM) protein family, such as TRIM32, contain RING, BBOX, and coiled-coil domains, as well as variable C-terminal domains. TRIM32 functions as an E3 ubiquitin ligase in the ubiquitin-proteasome system, which is responsible for protein degradation (summary by Locke et al., 2009).
Transcriptional activation of HIV-1 gene expression by the viral Tat protein requires the interaction of a cellular cofactor with the Tat activation domain. This domain consists of the cysteine-rich and core motifs of HIV-1 Tat and is functionally conserved in the distantly related Tat proteins of HIV-2 and EIAV. Fridell et al. (1995) used the yeast 2-hybrid system to identify TRIM32, which they called HT2A, a protein that specifically and precisely binds the activation domain of HIV-1 Tat and that can interact with the HIV-2 and EIAV Tat proteins in vivo. Fridell et al. (1995) demonstrated that the interaction between HT2A and the activation domain of HIV-1 Tat can be readily detected in the mammalian cell nucleus. They isolated the HT2A cDNA from a HeLa cell cDNA library and found that it contains an open reading frame encoding a predicted 653-amino acid protein of 72 kD. Using Northern blot analysis, they detected a major, approximately 3.7-kb HT2A transcript and a minor, approximately 2.7-kb HT2A transcript in all examined tissues. HT2A contains an N-terminal C3HC4 zinc finger motif, indicating that it is a member of the ring finger family (see RING1, 602045) which includes transcription factors, nucleic acid binding proteins, and oncogenes. HT2A is most similar to the ring finger subfamily that includes RFP (602165), PML (102578), T18, RPT1, and Ro autoantigen (600063) since it contains a cysteine/histidine cluster and a heptad repeat of hydrophobic residues that is predicted to form a coiled-coil structure. The unique C-terminal region of HT2A is necessary and sufficient for binding to Tat. Fridell et al. (1995) suggested that HT2A may play a significant role in mediating the biologic activity of the HIV-1 Tat protein in vivo.
Locke et al. (2009) stated that the TRIM32 protein contains a RING zinc finger domain, BBOX domain, BBC domain, and 6 C-terminal NHL domains.
Frosk et al. (2002) reported that the TRIM32 gene contains 2 exons.
Frosk et al. (2002) determined that the TRIM32 gene maps to chromosome 9q31-q33, between markers D9S1126 and D9S737. TRIM32 overlaps with intron 12 of the ASTN2 gene (612856) on the opposite strand.
Using short tandem repeat polymorphism (STRP) and single-nucleotide polymorphism (SNP) microarray genotyping, Chiang et al. (2006) identified the TRIM32 gene within a 2.4-Mb region on chromosome 9q33.1 linked to the Bardet-Biedl syndrome (209900) phenotype.
Locke et al. (2009) showed that TRIM32 is a widely expressed ubiquitin ligase that is localized to the Z-line in skeletal muscle. TRIM32 bound and ubiquitinated dysbindin, augmenting its degradation. Knockdown of TRIM32 in myoblasts resulted in elevated levels of dysbindin (DTNBP1; 607145). The D487N (602290.0001) and R394H (602290.0004) mutant proteins impaired ubiquitin ligase activity towards dysbindin and were mislocalized in heterologous cells. The D487N mutant could bind to both dysbindin and its ubiquitin-conjugating E2 enzyme but was defective in monoubiquitination. Locke et al. (2009) concluded that TRIM32 is a regulator of dysbindin and that TRIM32 mutations may impair substrate ubiquitination.
Using an approach that combined screening of candidate genes with a CGH array and massively parallel sequencing, Nectoux et al. (2015) identified 2 patients with LGMDR8 with homozygous or compound heterozygous mutations in the TRIM32 gene. In the first patient, one allele had a frameshift mutation (602290.0006), confirmed by Sanger sequencing, and the other allele had a 124.4-kb deletion that included the entire TRIM32 gene. The second patient, born to nonconsanguineous parents, had a homozygous 336-kb deletion including the TRIM32 gene. The deletions in both patients, which were confirmed by quantitative PCR, included part of the ASTN2 gene (612856). Analysis of the breakpoints showed that the 5-prime boundaries of both deletions were located within regions enriched with genomic repeats, possibly making rearrangements and deletions more likely to occur. Parents were not available for study for either patient.
Limb-Girdle Muscular Dystrophy, Autosomal Recessive 8
Autosomal recessive limb-girdle muscular dystrophy-8 (LGMDR8; 254110), previously symbolized LGMD2H, is a mild autosomal recessive myopathy that was first described in the Hutterite population of Manitoba, Canada. Frosk et al. (2002) narrowed the map assignment of the gene to a region of 560 kb on 9q and found that the region contains 4 known genes, including the TRIM32 gene. All affected individuals were homozygous for an asp487-to-asn (D487N; 602290.0001) mutation in TRIM32. The mutation occurred in an NHL (named after the proteins NCL1, HT2A, and LIN-41) domain at a position that is highly conserved. NHL domains are involved in protein-protein interactions. The domain structure of the TRIM32 protein suggested that it may be an E3-ubiquitin ligase. This may represent a novel pathogenic mechanism for muscular dystrophy.
Saccone et al. (2008) identified homozygous mutations in the TRIM32 gene (see, e.g., 602290.0003; 602290.0004) in non-Hutterite patients with LGMD2H. Both mutations occurred in the NHL domain. In vitro functional expression studies showed that these mutations abrogated TRIM32 self-interaction and UBE2N (603679) binding, indicating a dramatic effect on protein folding. In contrast, in vitro studies showed that the BBS P130S mutation retained the ability to self-interact, suggesting a different pathogenic mechanism in BBS.
Using comparative genomic hybridization (CGH) and sequencing of the TRIM32 gene in a 35-year-old woman with LGMDR8, Neri et al. (2013) identified compound heterozygous mutations: a nonsense mutation (R316X; 602290.0005) in the C-terminal NHL domain of TRIM32 on one allele and a deletion including the entire TRIM32 gene on the other allele. The precise breakpoints of the deletion could not be defined.
Using an approach that combined screening of candidate genes with a CGH array and massively parallel sequencing, Nectoux et al. (2015) identified a patient with LGMDR8 who had a frameshift mutation in the TRIM32 gene (c.160delC; 602290.0006), confirmed by Sanger sequencing, and a 124.4-kb deletion that included the entire TRIM32 gene and part of the ASTN2 gene (612856); see CYTOGENETICS. The deletion was confirmed by quantitative PCR. The parents were not available for study.
Bardet-Biedl Syndrome 11
Bardet-Biedl syndrome (BBS; see 209900) is a pleiotropic autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal abnormalities, learning disabilities, and hypogenitalism. The disorder displays extensive genetic heterogeneity. Chiang et al. (2006) used high density SNP genotyping to identify the disease-causing gene in a single small consanguineous Israeli Bedouin BBS family (BBS11; 615988) in which linkage studies failed to identify a disease locus. SNP genotyping revealed a homozygous candidate region. Mutation analysis in the region of homozygosity identified a homozygous missense mutation in a conserved B-box domain of TRIM32 (P130S; 602290.0002). Functional analysis of this gene in zebrafish and expression correlation analyses among other BBS genes in an expression quantitative trait loci dataset demonstrated that TRIM32 is a BBS gene. This study showed the value of high density SNP genotyping for homozygosity mapping and the use of expression correlation data for evaluation of candidate genes, and identified the involvement of the proteasome degradation pathway in BBS. The ubiquitin/proteasome system had not been implicated in this disorder. Another TRIM32 variant, a missense mutation associated with autosomal recessive limb girdle muscular dystrophy (D487N; 602290.0001), does not affect the E3 ubiquitin ligase activity, whereas disruption of the TRIM32 coiled-coil domain, as in the P130S mutation, reduces the binding affinity to myosin (Kudryashova et al., 2005).
Kudryashova et al. (2009) generated a Trim32-null mouse model of human muscular dystrophy phenotypes. Histologic analysis of Trim32-null skeletal muscles revealed mild myopathic changes. Electron microscopy showed areas with Z-line streaming and a dilated sarcotubular system with vacuoles, replicating the phenotypes of LGMD2H and sarcotubular myopathy. The level of Trim32 expression in normal mouse brain exceeded that observed in skeletal muscle by more than 100-fold. Analysis of Trim32-null neural tissue revealed a decreased concentration of neurofilaments and a reduction in myelinated motor axon diameters. The axonal changes suggested a shift toward a slower motor unit type. Trim32-null soleus muscle expressed an elevated type I slow myosin isotype with a concomitant reduction in the type II fast myosin. Kudryashova et al. (2009) suggested that muscular dystrophy due to TRIM32 mutation may involve both neurogenic and myogenic characteristics.
Frosk et al. (2002) found homozygosity for an asp487-to-asn (D487N) missense mutation in the TRIM32 gene as a causative mutation in the mild autosomal recessive myopathy observed in Manitoba Hutterites (LGMDR8; 254110). Frosk et al. (2002) stated that of 60 cases of LGMD studied in Manitoba Hutterites, most were caused by the D487N mutation.
Schoser et al. (2005) identified the homozygous D487N mutation in the patients reported by Jerusalem et al. (1973) and Muller-Felber et al. (1999), confirming that they had LGMDR8. In addition, haplotype analysis showed that all LGMDR8 patients shared the same haplotype, suggesting that the mutation arose before the emergence of the Hutterite religion in central Europe in the 16th century. Schoser et al. (2005) noted the phenotypic variability caused by the same mutation.
Frosk et al. (2005) reported a Hutterite family in which 2 boys, aged 7 and 10 years, were homozygous for both the D487N mutation and an LGMD2I (LGMDR9; 607155)-related FKRP mutation (L276I; 606596.0004). Although they presented at an early age with exercise intolerance and increased serum creatine kinase, the clinical phenotype was not significantly more severe than that of patients with isolated LGMD2H or LGMD2I. Both parents and 3 other sibs were homozygous for the D487N mutation, with highly variable phenotypic expression.
In vitro functional expression studies by Saccone et al. (2008) demonstrated that D487N-mutant protein lost the ability to homodimerize and showed inhibited binding to full-length UBE2N (603679). The consequences of this mutation were similar to complete deletion of the coiled coil-NHL domains, suggesting a dramatic effect on protein folding.
Locke et al. (2009) showed that D487N-mutant protein impaired TRIM32 ubiquitin ligase activity towards dysbindin (DTNBP1; 607145) and mislocalized in heterologous cells. The D487N mutant could bind to both dysbindin and its ubiquitin-conjugating E2 enzyme but was defective in monoubiquitination. Locke et al. (2009) suggest that D487N mutation may impair substrate ubiquitination.
Among 1,493 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 228 heterozygotes and 9 homozygotes for the D487N mutation in the TRIM32 gene, for a frequency of 0.153, or 1 in 6.5. The carrier frequency in other populations was unknown, with only 2 non-Hutterite cases having been reported (Schoser et al., 2005). The 9 homozygous individuals ranged in age from 10 to 42 years, and were unaware of their status.
By homozygosity mapping using high-density SNP genotyping, Chiang et al. (2006) identified the TRIM32 gene as the site of mutations causing Bardet-Biedl syndrome (BBS11; 615988) in a small consanguineous Israeli Bedouin family. The specific mutation was a change of codon 130 from CCT (pro) to TCT (ser). The substitution was present in homozygous state in the affected individuals.
In vitro functional expression studies by Saccone et al. (2008) demonstrated that the P130S-mutant protein maintained self-interaction ability.
In a 44-year-old Croatian woman with limb-girdle muscular dystrophy type 2H (LGMDR8; 254110), Saccone et al. (2008) identified a homozygous 1-bp deletion (1559delC) in the TRIM32 gene within a conserved region of the NHL domain, resulting in frameshift and premature termination. The patient had slowly progressive proximal muscle weakness and wasting, respiratory weakness, and chronic keratitis. In vitro functional expression studies showed that truncated protein lost the ability to homodimerize and showed inhibited binding to full-length UBE2N (603679).
In a man with limb-girdle muscular dystrophy type 2H (LGMDR8; 254110), Saccone et al. (2008) identified a homozygous 1180G-A transition in the TRIM32 gene, resulting in an arg394-to-his (R394H) substitution in a conserved residue of an NHL domain. Disease onset was in the third decade with weakness and paresthesias. He had marked proximal weakness and atrophy, as well as respiratory weakness, and lost the ability to walk at age 64 after prolonged immobility for other causes. A second patient was found to be heterozygous for the R394H mutation. He was 73 years old and had mild symptoms with no respiratory involvement. In vitro functional expression studies showed that R394H-mutant protein lost the ability to homodimerize and showed inhibited binding to full-length UBE2N (603679).
Locke et al. (2009) showed that R394H-mutant protein impaired TRIM32 ubiquitin ligase activity towards dysbindin and mislocalized in heterologous cells, but was able to self-associate. Coexpression of wildtype and R394H-mutant TRIM32 reduced the level of dysbindin monoubiquitination, possibly indicating that R394H may compromise function of the wildtype protein.
By sequencing of the TRIM32 gene in a 35-year-old Italian woman with autosomal recessive limb-girdle muscular dystrophy (LGMDR8; 254110), Neri et al. (2013) identified a heterozygous c.1837C-T transition, resulting in an arg316-to-ter (R316X) in the C-terminal NHL domain. The mutation was found in compound heterozygosity with a deletion of the entire TRIM32 gene, identified by a custom comparative genomic hybridization (CGH) array. The breakpoints of the deletion could not be defined.
Using a combined approach of comparative genomic hybridization array and massively parallel sequencing, Nectoux et al. (2015) identified a patient with autosomal recessive limb-girdle muscular dystrophy (LGMDR8; 254110) who was compound heterozygous for a 1-bp deletion (c.1603delC, NM_012210.3) in the TRIM32 gene, resulting in a frameshift (Leu535SerfsTer21), and a 124.4-kb deletion including the entire TRIM32 gene and part of the ASTN2 gene (612856). The patient had a mild phenotype of progressive limb-girdle muscular dystrophy as typically seen in patients with LGMDR8.
Chiang, A. P., Beck, J. S., Yen, H.-J., Tayeh, M. K., Scheetz, T. E., Swiderski, R. E., Nishimura, D. Y., Braun, T. A., Kim, K.-Y. A., Huang, J., Elbedour, K., Carmi, R., Slusarski, D. C., Casavant, T. L., Stone, E. M., Sheffield, V. C. Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc. Nat. Acad. Sci. 103: 6287-6292, 2006. [PubMed: 16606853] [Full Text: https://doi.org/10.1073/pnas.0600158103]
Chong, J. X., Ouwenga, R., Anderson, R. L., Waggoner, D. J., Ober, C. A population-based study of autosomal-recessive disease-causing mutations in a founder population. Am. J. Hum. Genet. 91: 608-620, 2012. [PubMed: 22981120] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.007]
Fridell, R. A., Harding, L. S., Bogerd, H. P., Cullen, B. R. Identification of a novel human zinc finger protein that specifically interacts with the activation domain of lentiviral Tat proteins. Virology 209: 347-357, 1995. [PubMed: 7778269] [Full Text: https://doi.org/10.1006/viro.1995.1266]
Frosk, P., Del Bigio, M. R., Wrogemann, K., Greenberg, C. R. Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I. Europ. J. Hum. Genet. 13: 978-982, 2005. [PubMed: 15886712] [Full Text: https://doi.org/10.1038/sj.ejhg.5201436]
Frosk, P., Weiler, T., Nylen, E., Sudha, T., Greenberg, C. R., Morgan, K., Fujiwara, T. M., Wrogemann, K. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Am. J. Hum. Genet. 70: 663-672, 2002. [PubMed: 11822024] [Full Text: https://doi.org/10.1086/339083]
Jerusalem, F., Engel, A. G., Gomez, M. R. Sarcotubular myopathy. Neurology 23: 897-906, 1973. [PubMed: 4269389] [Full Text: https://doi.org/10.1212/wnl.23.9.897]
Kudryashova, E., Kudryashov, D., Kramerova, I., Spencer, M. J. Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin. J. Molec. Biol. 354: 413-424, 2005. [PubMed: 16243356] [Full Text: https://doi.org/10.1016/j.jmb.2005.09.068]
Kudryashova, E., Wu, J., Havton, L. A., Spencer, M. J. Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic component. Hum. Molec. Genet. 18: 1353-1367, 2009. [PubMed: 19155210] [Full Text: https://doi.org/10.1093/hmg/ddp036]
Locke, M., Tinsley, C. L., Benson, M. A., Blake, D. J. TRIM32 is an E3 ubiquitin ligase for dysbindin. Hum. Molec. Genet. 18: 2344-2358, 2009. [PubMed: 19349376] [Full Text: https://doi.org/10.1093/hmg/ddp167]
Muller-Felber, W., Schlotter, B., Topfer, M., Ketelsen, U.-P., Muller-Hocker, J., Pongratz, D. Phenotypic variability in two brothers with sarcotubular myopathy. (Letter) J. Neurol. 246: 408-411, 1999. [PubMed: 10399877] [Full Text: https://doi.org/10.1007/s004150050374]
Nectoux, J., de Cid, R., Baulande, S., Leturcq, F., Urtizberea, J. A., Penisson-Besnier, I., Nadaj-Pakleza, A., Roudaut, C., Criqui, A., Orhant, L., Peyroulan, D., Ben Yaou, R., and 11 others. Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing. Europ. J. Hum. Genet. 23: 929-934, 2015. [PubMed: 25351777] [Full Text: https://doi.org/10.1038/ejhg.2014.223]
Neri, M., Selvatici, R., Scotton, C., Trabanelli, C., Armaroli, A., De Grandis, D., Levy, N., Gualandi, F., Ferlini, A. A patient with limb girdle muscular dystrophy carries a TRIM32 deletion, detected by a novel CGH array, in compound heterozygosis with a nonsense mutation. Neuromusc. Disord. 23: 478-482, 2013. [PubMed: 23541687] [Full Text: https://doi.org/10.1016/j.nmd.2013.02.003]
Saccone, V., Palmieri, M., Passamano, L., Piluso, G., Meroni, G., Politano, L., Nigro, V. Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H. Hum. Mutat. 29: 240-247, 2008. [PubMed: 17994549] [Full Text: https://doi.org/10.1002/humu.20633]
Schoser, B. G. H., Frosk, P., Engel, A. G., Klutzny, U., Lochmuller, H., Wrogemann, K. Commonality of TRIM32 mutation in causing sarcotubular myopathy and LGMD2H. Ann. Neurol. 57: 591-595, 2005. [PubMed: 15786463] [Full Text: https://doi.org/10.1002/ana.20441]