Alternative titles; symbols
HGNC Approved Gene Symbol: TRIM37
SNOMEDCT: 81604003;
Cytogenetic location: 17q22 Genomic coordinates (GRCh38): 17:58,967,201-59,106,880 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q22 | Mulibrey nanism | 253250 | Autosomal recessive | 3 |
The TRIM37 gene encodes a member of the RING B-box coiled-coil (RBCC) family of zinc finger proteins, whose members are involved in diverse cellular functions such as developmental patterning and oncogenesis (Avela et al., 2000).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned TRIM37, which they designated KIAA0898. The deduced protein contains 979 amino acids. RT-PCR ELISA detected intermediate expression in brain, liver, testis, and ovary, low expression in heart, lung, skeletal muscle, and kidney, and little to no expression in pancreas and spleen.
Avela et al. (2000) refined the critical region for mulibrey nanism (253250) to an 800-kb region on chromosome 17q22-q23. They identified the KIAA0898 cDNA as corresponding to the gene, symbolized MUL. The MUL protein contains a RING finger followed by a B-box motif and a coiled-coil domain. The RING finger and B-box domains chelate zinc and are thought to be involved in protein-protein and/or protein-nucleic acid interactions. Two nuclear localization signals, PAVEKRR and KRRK, are present at amino acid positions 847 and 851, respectively. Northern blot analysis detected ubiquitous expression of a 4.4-kb transcript. Avela et al. (2000) predicted that MUL is a 108-kD nuclear protein. They identified homologous mouse and rat ESTs.
By searching for sequences containing TRAF-like domains (see TRAF1; 601711), followed by RT-PCR of Jurkat human T-cell total RNA, Zapata et al. (2001) cloned TRIM37, which they called MUL. The deduced protein contains an N-terminal RING finger domain, followed by a zinc finger B box, 2 coiled-coil regions, a central TRAF-like domain, a third coiled-coil domain, an acidic domain, 2 nuclear localization signals, and a second acidic domain. MUL localized to cytosolic bodies in transfected COS-7 cells. Mutation analysis indicated that the N-terminal domains, but not the TRAF-like domain, were required for punctate intracellular distribution.
Zapata et al. (2001) found that the TRAF-like domain of MUL could interact in vitro with all TRAF proteins tested and with itself. The TRAF-like domain also suppressed NFKB (see 164011) induction by TRAF2 (601895), TRAF6 (602355), and some TRAF-binding TNF receptors (see 191190).
Kallijarvi et al. (2002) used transiently transfected cells and antibodies raised against the predicted TRIM37 protein to characterize the TRIM37 product and to determine its intracellular localization. They showed that the human TRIM37 cDNA encodes a peroxisomal protein with an apparent molecular weight of 130 kD. Peroxisomal localization was compromised in mutant protein representing the major Finnish TRIM37 mutation (605073.0001) but was retained in the protein representing the minor Finnish mutation (605073.0002). Colocalization of endogenous TRIM37 with peroxisomal markers was observed by double immunofluorescence staining. In human tissue sections, TRIM37 showed a granular cytoplasmic pattern. Endogenous TRIM37 was not imported into peroxisomes in fibroblasts with mutants of peroxin-1 (PEX1; 602136) or peroxin-5 (PEX5; 600414), but was imported normally in peroxin-7 (PEX7; 601757)-deficient fibroblasts, giving further evidence for peroxisomal localization of TRIM37. Fibroblasts derived from patients with mulibrey nanism lack C-terminal TRIM37 immunoreactivity but stain normally for both peroxisomal matrix and membrane markers, suggesting apparently normal peroxisome biogenesis in the fibroblasts of these patients. Taken together, this molecular evidence was thought to indicate unequivocally that TRIM37 is located in the peroxisomes, and that mulibrey nanism should be classified as a peroxisomal disorder.
Bhatnagar et al. (2014) reported that TRIM37 monoubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. They found that in human breast cancer cell lines containing amplified 17q23, TRIM37 is upregulated and, reciprocally, the major H2A ubiquitin ligase RNF2 (608985) is downregulated. ChIP-chip experiments in 17q23-amplified breast cancer cells identified many genes, including multiple tumor suppressors, whose promoters were bound by TRIM37 and enriched for ubiquitinated H2A. However, unlike RNF2, which is a subunit of polycomb repressive complex-1 (PRC1), Bhatnagar et al. (2014) found that TRIM37 associates with PRC2. TRIM37, PRC2, and PRC1 are cobound to specific target genes, resulting in their transcriptional silencing. RNAi-mediated knockdown of TRIM37 results in loss of ubiquitinated H2A, dissociation of PRC1 and PRC2 from target promoters, and transcriptional reactivation of silenced genes. Knockdown of TRIM37 in human breast cancer cells containing amplified 17q23 substantially decreases tumor growth in mouse xenografts; conversely, ectopic expression of TRIM37 renders nontransformed cells tumorigenic. Bhatnagar et al. (2014) concluded that their results revealed TRIM37 as an oncogenic H2A ubiquitin ligase that is overexpressed in a subset of breast cancers and promotes transformation by facilitating silencing of tumor suppressors and other genes.
By merit of its identification within the critical region for mulibrey nanism (Avela et al., 2000), the TRIM37 gene maps to chromosome 17q22-q23.
In patients with mulibrey nanism (MUL; 253250) from Finland, Czechoslovakia, and the United States, Avela et al. (2000) identified 4 independent mutations in the MUL gene, each of which caused a frameshift and predicted premature termination of the protein.
In a Turkish family, Jagiello et al. (2003) identified a novel mutation (605073.0005) as the basis of mulibrey nanism. The mutation was identified by RT-PCR and direct cDNA sequencing.
In an 11-year-old boy with MUL, Bruzzaniti et al. (2020) identified a splice site mutation in the TRIM37 gene inherited from the father (605073.0008) and a 17q22 deletion including the TRIM37 gene inherited from the mother.
Avela et al. (2000) found that the major Finnish mutation causing mulibrey nanism (MUL; 253250), found in 98 of 100 Finnish MUL chromosomes, all with the same haplotype, was a 5-bp deletion at nucleotides 493-497 of the MUL cDNA. Sequencing of genomic DNA disclosed an A-to-G transition altering the consensus dinucleotide sequence of the 3-prime splice site (AG) at position -2 from nucleotide 493 of the cDNA and resulting in aberrant splicing at the next AG site. The cDNA deletion caused a frameshift and predicted a stop codon 10 codons downstream.
Avela et al. (2000) found that each of 2 Finnish patients with mulibrey nanism (MUL; 253250) were compound heterozygotes for the major Finnish mutation (605073.0001) and a 1-bp deletion of a G at nucleotide 2212 of the cDNA. The mutation resulted in a frameshift and predicted a stop codon 30 codons downstream. These patients were not members of the same sibship nor were they closely related.
In a Czech patient with mulibrey nanism (MUL; 253250) who was homozygous for a 'private' haplotype, Avela et al. (2000) identified a homozygous 5-bp deletion of ACTTT at nucleotides 838-842 of the MUL cDNA, leading to a frameshift and a stop codon 55 codons downstream.
In an American patient with mulibrey nanism (MUL; 253250), Avela et al. (2000) found homozygosity for a 1-bp insertion of an A at nucleotide 1346 of the MUL cDNA.
In a Turkish family studied in Germany, Jagiello et al. (2003) found that mulibrey nanism (MUL; 253250) was cosegregating with a mutation in the TRIM37 gene. The mutation was an 8-bp deletion, removing nucleotides 855-862, which was situated in proximity to the 'Czech' mutation (605073.0003), a 5-bp deletion removing nucleotides 838-842. The mutated allele had altered splicing. Jagiello et al. (2003) could identify several splice variants, and characterized 5 of these.
In an Australian child with mulibrey nanism (MUL; 253250), Hamalainen et al. (2006) identified compound heterozygosity for 2 mutations in the TRIM37 gene: a 326G-C transversion, resulting in a cys109-to-ser (C109S) substitution in the B-box domain, and an 860G-A transition in the splice donor site of exon 10, resulting in skipping of exon 10 and in-frame deletion of 17 amino acids from the TRAF domain (605073.0007). Studies in COS-1 cells showed that both mutant proteins had diffuse cytoplasmic staining and retained ubiquitin ligase activity. The child first presented at age 10 months with short stature and facial dysmorphism and developed Wilms tumor at age 18 months.
For discussion of the 860G-A mutation in the TRIM37 gene that was found in compound heterozygous state in a patient with mulibrey nanism (MUL; 253250) by Hamalainen et al. (2006), see 605073.0006.
In an 11-year-old boy with mulibrey nanism (MUL; 253250), Bruzzaniti et al. (2020) identified a paternally inherited splice site mutation in intron 18 (c.1949-12A-G) of the TRIM37 gene and a maternally inherited deletion on chromosome 17q22 (chr17:57,086,110-57,229,241) including the TRIM37 gene. The mutation was found by exome sequencing and the deletion was found by SNP array. TRIM37 protein expression was reduced in patient-derived stimulated and unstimulated CD4+ and CD8+ cells, with a greater reduction in CD4+ cells.
Avela, K., Lipsanen-Nyman, M., Idanheimo, N., Seemanova, E., Rosengren, S., Makela, T. P., Perheentupa, J., de la Chapelle, A., Lehesjoki, A.-E. Gene encoding a new RING-B-box-coiled-coil protein is mutated in mulibrey nanism. Nature Genet. 25: 298-301, 2000. [PubMed: 10888877] [Full Text: https://doi.org/10.1038/77053]
Bhatnagar, S., Gazin, C., Chamberlain, L., Ou, J., Zhu, X., Tushir, J. S., Virbasius, C.-M., Lin, L., Zhu, L. J., Wajapeyee, N., Green, M. R. TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein. Nature 516: 116-120, 2014. [PubMed: 25470042] [Full Text: https://doi.org/10.1038/nature13955]
Bruzzaniti, S., Cirillo, E., Prencipe, R., Giardino, G., Lepore, M. T., Garziano, F., Perna, F., Procaccini, C., Mascolo, L., Pagano, C., Fattorusso, V., Mozzillo, E., Bifulco, M., Matarese, G., Franzese, A., Pignata, C., Galgani, M. CD4+ T cell defects in a mulibrey patient with specific TRIM37 mutations. Front. Immun. 11: 1742, 2020. [PubMed: 33042106] [Full Text: https://doi.org/10.3389/fimmu.2020.01742]
Hamalainen, R. H., Mowat, D., Gabbett, M. T., O'Brien, T. A., Kallijarvi, J., Lehesjoki, A.-E. Wilms' tumor and novel TRIM37 mutations in an Australian patient with mulibrey nanism. Clin. Genet. 70: 473-479, 2006. [PubMed: 17100991] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00700.x]
Jagiello, P., Hammans, C., Wieczorek, S., Arning, L., Stefanski, A., Strehl, H., Epplen, J. T., Gencik, M. A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity. Hum. Mutat. 21: 630-635, 2003. [PubMed: 12754710] [Full Text: https://doi.org/10.1002/humu.10220]
Kallijarvi, J., Avela, K., Lipsanen-Nyman, M., Ulmanen, I., Lehesjoki, A.-E. The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder. Am. J. Hum. Genet. 70: 1215-1228, 2002. [PubMed: 11938494] [Full Text: https://doi.org/10.1086/340256]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 355-364, 1998. [PubMed: 10048485] [Full Text: https://doi.org/10.1093/dnares/5.6.355]
Zapata, J. M., Pawlowski, K., Haas, E., Ware, C. F., Godzik, A., Reed, J. C. A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains. J. Biol. Chem. 276: 24242-24252, 2001. [PubMed: 11279055] [Full Text: https://doi.org/10.1074/jbc.M100354200]