HGNC Approved Gene Symbol: UFM1
Cytogenetic location: 13q13.3 Genomic coordinates (GRCh38) : 13:38,349,851-38,363,619 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q13.3 | Leukodystrophy, hypomyelinating, 14 | 617899 | Autosomal recessive | 3 |
UFM1 is a ubiquitin-like protein that is conjugated to target proteins (i.e., UFMylation) by E1-like activating enzyme UBE1DC1 (UBA5; 610552) and E2-like conjugating enzyme UFC1 (610554) in a manner analogous to ubiquitylation (see UBE2M, 603173) (Komatsu et al., 2004).
Using coimmunoprecipitation with FLAG-tagged ubiquitin-like activating enzyme UBE1DC1 expressed in HEK293 cells, Komatsu et al. (2004) purified fragments of proteins physically associated with UBE1DC1. By database analysis with these fragments followed by PCR of human liver cDNA, they cloned UFM1 and UFC1. The deduced 85-amino acid UFM1 protein has a predicted molecular mass of 9.1 kD and shares no overall sequence identity to ubiquitin or other modifiers; however, UFM1 and ubiquitin (UBB; 191339) share highly similar predicted tertiary structures. Western blot analysis of mouse tissues with anti-UFM1 serum detected expression of mouse Ufm1 protein in all tissues examined, including brain, heart, lung, liver, and kidney. Immunocytochemistry of HeLa cells using anti-UFM1 serum showed predominant distribution of UFM1 in the nucleus, with diffuse staining in the cytoplasm. Immunoreactivity within the nucleus localized as dot-like structures that may represent UFM1 conjugates.
Using Myc-tagged UFM1 coexpressed with FLAG-tagged UBE1DC1, FLAG-tagged UFC1, and mutant constructs, as well as in vitro UFM1 conjugation assays, Komatsu et al. (2004) showed that UFM1 is a ubiquitin-like protein that is activated by the E1-like enzyme UBE1DC1 by formation of a thioester bond and conjugated by the E2-like enzyme UFC1 with a similar thioester linkage. Using FLAG- and His-tagged UFM1 constructs in HEK293 followed by purification and analysis of protein complexes formed, Komatsu et al. (2004) showed that UFM1 is conjugated to target proteins in cells by a covalent linkage, possibly via an isopeptide bond between the C-terminal gly83 of UFM1 and a lysine residue in the target protein.
By reconstitution experiments, Peter et al. (2022) showed that UFL1 (613372) and UFBP1 (DDRGK1; 616177) formed an active E3 ligase complex that efficiently UFMylated substrates and assembled poly-UFM1 chains that were lys69-linked. Further analysis revealed that UFL1/UFBP1 was a scaffold-type ligase complex that activated UFC1 for aminolysis. Truncation analysis revealed that the 3 tandem WH domains of UFL1/UFBP1 were sufficient for E3 ligase activity, with additional regions also required for substrate modification. CDK5RAP3 (608202) formed an integral complex with UFL1/UFBP1 and functioned as a specificity determinant, keeping the ligase activity of the complex inhibited in the absence of substrate and directing ligase activity toward the ribosomal subunit RPL26 (603704).
In 16 patients with hypomyelinating leukodystrophy-14 (HLD14; 617899), Hamilton et al. (2017) identified a homozygous 3-bp deletion in the promoter region of the UFM1 gene (610553.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Most of the patients were of Roma descent, and haplotype analysis indicated a founder effect. In vitro functional expression studies using a luciferase reporter in different cell lines showed that the mutation significantly reduced promoter and transcriptional activity in certain neuronal cell lines (SY5Y and U373), but not in other cell lines (HeLa and HOF-F2).
In 4 patients from 2 Sudanese families with HLD14, Nahorski et al. (2018) identified a homozygous missense mutation in the UFM1 gene (R81C; 610553.0002). The mutation was found by exome sequencing. In vitro functional expression assays demonstrated that the mutation decreased the ability of UFM1 to form thioester bonds with UBA5 and UFC1. The decrease in function was consistent with a hypomorphic allele, and Nahorski et al. (2018) suggested that complete loss of function would be embryonic lethal. The findings suggested that impaired posttranslational protein ufmylation results in neurodevelopmental defects.
Muona et al. (2016) found that conditional knockdown of Ufm1 in mouse brain resulted in death within the first day of life. Postmortem examination showed microcephaly and markers of increased neuronal apoptosis in specific brain regions.
In 16 patients with hypomyelinating leukodystrophy-14 (HLD14; 617899), Hamilton et al. (2017) identified a homozygous 3-bp deletion in the promoter region of the UFM1 gene (c.-273_-271delTCA, NM_001286704.1). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Most of the patients were of Roma descent, and haplotype analysis indicated a founder effect. Screening of 670 Roma controls revealed 30 mutation carriers, yielding a carrier rate of 4.5% for the allele; 1 individual was homozygous for the mutation, but retrospective studies indicated that he was affected. Carrier rate in the specific community where the homozygous individual was from showed a carrier rate of about 25%. In vitro functional expression studies using a luciferase reporter in different cell lines showed that the mutation significantly reduced promoter and transcriptional activity in certain neuronal cell lines (SY5Y and U373), but not in other cell lines (HeLa and HOF-F2).
In 4 patients from 2 consanguineous Sudanese families with hypomyelinating leukodystrophy-14 (HLD14; 617899), Nahorski et al. (2018) identified a homozygous c.241C-T transition (c.241C-T, NM_016617.3) in the UFM1 gene, resulting in an arg81-to-cys (R81C) substitution at a highly conserved residue in the C-terminal tail that is essential for its adenylation and subsequent thioester formation with UBA5 (610552). The mutation was found by exome sequencing. In vitro functional expression assays demonstrated that the mutation decreased the ability of UFM1 to form thioester bonds with UBA5 and UFC1 (610554). The decrease in function was consistent with a hypomorphic allele, and Nahorski et al. (2018) suggested that complete loss of function would be embryonic lethal. The findings suggested that impaired posttranslational protein ufmylation results in neurodevelopmental defects.
Hamilton, E. M. C., Bertini, E., Kalaydjieva, L., Morar, B., Dojcakova, D., Liu, J., Vanderver, A., Curiel, J., Persoon, C. M., Diodato, D., Pinelli, L., van der Meij, N. L., Plecko, B., Blaser, S., Wolf, N. I., Waisfisz, Q., Abbink, T. E. M., van der Knapp, M. S. UFM1 founder mutation in the Roma population causes recessive variant of H-ABC. Neurology 89: 1821-1828, 2017. [PubMed: 28931644] [Full Text: https://doi.org/10.1212/WNL.0000000000004578]
Komatsu, M., Chiba, T., Tatsumi, K., Iemura, S., Tanida, I., Okazaki, N., Ueno, T., Kominami, E., Natsume, T., Tanaka, K. A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO J. 23: 1977-1986, 2004. [PubMed: 15071506] [Full Text: https://doi.org/10.1038/sj.emboj.7600205]
Muona, M., Ishimura, R., Laari, A., Ichimura, Y., Linnankivi, T., Keski-Filppula, R., Herva, R., Rantala, H., Paetau, A., Poyhonen, M., Obata, M., Uemura, T., and 17 others. Biallelic variants in UBA5 link dysfunctional UFM1 ubiquitin-like modifier pathway to severe infantile-onset encephalopathy. Am. J. Hum. Genet. 99: 683-694, 2016. [PubMed: 27545674] [Full Text: https://doi.org/10.1016/j.ajhg.2016.06.020]
Nahorski, M. S., Maddirevula, S., Ishimura, R., Alsahli, S., Brady, A. F., Begemann, A., Mizushima, T., Guzman-Vega, F. J., Obata, M., Ichimura, Y., Alsaif, H. S., Anazi, S., and 15 others. Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development. Brain 141: 1934-1945, 2018. [PubMed: 29868776] [Full Text: https://doi.org/10.1093/brain/awy135]
Peter, J. J., Magnussen, H. M., DaRosa, P. A., Millrine, D., Matthews, S. P., Lamoliatte, F., Sundaramoorthy, R., Kopito, R. R., Kulathu, Y. A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation. EMBO J. 41: e111015, 2022. [PubMed: 36121123] [Full Text: https://doi.org/10.15252/embj.2022111015]