Alternative titles; symbols
HGNC Approved Gene Symbol: OTUD4
Cytogenetic location: 4q31.21 Genomic coordinates (GRCh38): 4:145,133,650-145,180,589 (from NCBI)
Using PCR with a human immunodeficiency virus-1 (HIV-1)-infected human CD4 (186940)-positive T-cell line to isolate virus-host chimeric transcripts, Raineri and Senn (1992) identified OTUD4, which they called HIN1. The deduced 145-amino acid protein shares 32.5% identity with Drosophila Otu. Raineri and Senn (1992) noted that HIN1 may have been truncated at its 5-prime end by HIV-1 insertion. Expression of HIN1 was only detected in HIV-1-infected cells, suggesting that expression was due to insertional activation from the 3-prime long terminal repeat of HIV-1.
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Kikuno et al. (1999) cloned OTUD4, which they designated KIAA1046. The deduced protein contains 401 amino acids. RT-PCR ELISA detected highest expression in lung, with high levels also detected in testis, ovary, kidney, skeletal muscle, liver, heart, brain, fetal liver, and all specific adult brain regions examined. Expression was moderate in fetal brain and in adult pancreas and spleen.
Using radiation hybrid analysis, Kikuno et al. (1999) mapped the OTUD4 gene to chromosome 12. However, Gross (2023) mapped the OTUD4 gene to chromosome 4q31.21 based on an alignment of the OTUD4 sequence (GenBank BC118572) with the genomic sequence (GRCh38).
Associations Pending Confirmation
For discussion of a possible association between Gordon Holmes syndrome (212840) and mutation in the OTUD4 gene, see 611744.0001.
Margolin et al. (2013) injected splice-blocking morpholino oligonucleotides against the zebrafish genes rnf216 (609948) and otud4 and observed defects in the eye, optic tectum, and cerebellum. Combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by wildtype but not mutant human RNF216 or OTUD4 mRNA.
This variant is classified as a variant of unknown significance because its contribution to cerebellar ataxia and hypogonadotropic hypogonadism (Gordon Holmes syndrome; 212840) has not been confirmed.
In 3 affected sibs from a 7-generation consanguineous Palestinian family with cerebellar ataxia and hypogonadotropic hypogonadism, originally reported by Seminara et al. (2002), Margolin et al. (2013) identified homozygosity for 2 missense mutations in 2 genes: a c.998G-T transversion in the OTUD4 gene, resulting in a gly333-to-val (G333V) substitution at a conserved residue, and a missense mutation in the RNF216 gene (R751C; 609948.0001). The mutations segregated with disease in the family and neither was found in 672 Middle Eastern control chromosomes, including 36 Palestinian chromosomes; however, the OTUD4 G333V variant was detected in 2 of 13,006 chromosomes from the NHLBI Exome Sequencing Project. The phenotype of mutant zebrafish injected with splice-blocking morpholino oligonucleotides against rnf216 could be rescued by wildtype but not mutant OTUD4 mRNA, suggesting that the G333V mutation affects protein function. Sequencing of the RNF216 and OTUD4 genes in additional patients revealed no further mutations in the OTUD4 gene, although several patients had other mutations in RNF216 (see, e.g., 609948.0002-609948.0003).
Gross, M. B. Personal Communication. Baltimore, Md. 2/8/2023.
Kikuno, R., Nagase, T., Ishikawa, K., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 197-205, 1999. [PubMed: 10470851] [Full Text: https://doi.org/10.1093/dnares/6.3.197]
Margolin, D. H., Kousi, M., Chan, Y.-M., Lim, E. T., Schmahmann, J. D., Hadjivassiliou, M., Hall, J. E., Adam, I., Dwyer, A., Plummer, L., Aldrin, S. V., O'Rourke, J., and 9 others. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. New Eng. J. Med. 368: 1992-2003, 2013. [PubMed: 23656588] [Full Text: https://doi.org/10.1056/NEJMoa1215993]
Raineri, I., Senn, H.-P. HIV-1 promoter insertion revealed by selective detection of chimeric provirus-host gene transcripts. Nucleic Acids Res. 20: 6261-6266, 1992. [PubMed: 1475186] [Full Text: https://doi.org/10.1093/nar/20.23.6261]
Seminara, S. B., Acierno, J. S., Jr., Abdulwahid, N. A., Crowley, W. F., Jr., Margolin, D. H. Hypogonadotropic hypogonadism and cerebellar ataxia: detailed phenotypic characterization of a large, extended kindred. J. Clin. Endocr. Metab. 87: 1607-1612, 2002. [PubMed: 11932290] [Full Text: https://doi.org/10.1210/jcem.87.4.8384]