HGNC Approved Gene Symbol: UFD1
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:19,449,911-19,479,193 (from NCBI)
In a search for genes in the 22q11.2 region implicated in the DiGeorge syndrome (188400), Pizzuti et al. (1997) identified a gene whose functional features and tissue-specific expression suggested a distinct role in embryogenesis. Symbolized UFD1L by them (for ubiquitin fusion degradation 1-like), the gene encodes the human homolog of the yeast ubiquitin fusion degradation 1 (UFD1) protein that is involved in the degradation of ubiquitin fusion proteins (see 191339). Cloning and characterization of the murine homolog (Ufd1l) showed it to be expressed during embryogenesis in the eyes and in the inner ear primordia. These findings suggested to Pizzuti et al. (1997) that the proteolytic pathway recognizing ubiquitin fusion proteins for degradation is conserved in vertebrates and that UFD1L gene hemizygosity may be the cause of some of the CATCH22-associated developmental defects.
The basic helix-loop-helix transcription factor dHAND (HAND2; 602407) is required for survival of cells in the neural crest-derived branchial and aortic arch arteries and the right ventricle. Mice lacking endothelin-1 (EDN1; 131240) have cardiac and cranial neural crest defects typical of the 22q11 deletion syndrome and display downregulation of dHAND, suggesting that a molecular pathway involving dHAND may be disrupted in that syndrome. The HAND2, EDN1, and ET1 receptor (EDNRA; 131243) genes do not map to 22q11, the DiGeorge syndrome critical region, in humans. In a screen for mouse genes dependent on dHAND, Yamagishi et al. (1999) identified Ufd1l. Mouse Ufd1l (Yamagishi et al., 1999) and chick Ufd1l (Yamagishi et al., 2003) are specifically expressed in most tissues affected in patients with the DiGeorge (22q11 deletion) syndrome. Yamagishi et al. (2003) demonstrated that functional attenuation of chick Ufd1l in cardiac neural crest cells resulted in an increased incidence of conotruncal septation defects.
Olmos et al. (2015) demonstrated that the endosomal sorting complex required for transport-III (ESCRT-III) machinery localizes to sites of annular fusion in the forming nuclear envelope in human cells, and is necessary for proper postmitotic nucleocytoplasmic compartmentalization. The ESCRT-III component CHMP2A (610893) is directed to the forming nuclear envelope through binding to CHMP4B (610897), and provides an activity essential for nuclear envelope reformation. Localization also requires the p97 complex (see 601023) member UFD1. Olmos et al. (2015) concluded that their results described a novel role for the ESCRT machinery in cell division and demonstrated a conservation of the machineries involved in topologically equivalent mitotic membrane remodeling events.
Pizzuti et al. (1997) identified the UFD1L gene in chromosome 22q11.2.
Yamagishi et al. (1999) found that the human UFD1L gene was deleted in all 182 patients studied with the 22q11 deletion, and a smaller deletion of approximately 20 kb that removed exons 1 to 3 of UFD1L was found in 1 individual with features typical of 22q11 deletion syndrome. In the individual (J.F.) with the smaller deletion, Yamagishi et al. (1999) showed that the CDC45L gene (603465), which is immediately telomeric of UFD1L, was the site of the deletion in the region between exons 5 and 6 of the 5-prime breakpoint. They considered that the deletion in CDC45L may act as a modifier of the phenotype in patient J.F. UFD1L and CDC45L are transcribed in opposite directions. The deletion left exons 4 to 12 of UFD1L intact; the first 5 exons of CDC45L were deleted. Patient J.F. had nearly all of the features commonly associated with the 2-Mb 22q11 deletion. Four days after birth the patient was diagnosed with interrupted aortic arch, persistent truncus arteriosus, cleft palate, small mouth, low-set ears, broad nasal bridge, neonatal hypocalcemia, T-lymphocyte deficiency, and syndactyly of her toes. The deletion was not present in her parents or in 100 control subjects.
Olmos, Y., Hodgson, L., Mantell, J., Verkade, P., Carlton, J. G. ESCRT-III controls nuclear envelope reformation. Nature 522: 236-239, 2015. [PubMed: 26040713] [Full Text: https://doi.org/10.1038/nature14503]
Pizzuti, A., Novelli, G., Ratti, A., Amati, F., Mari, A., Calabrese, G., Nicolis, S., Silani, V., Marino, B., Scarlato, G., Ottolenghi, S., Dallapiccola, B. UFD1L, a developmentally expressed ubiquitination gene, is deleted in CATCH 22 syndrome. Hum. Molec. Genet. 6: 259-265, 1997. [PubMed: 9063746] [Full Text: https://doi.org/10.1093/hmg/6.2.259]
Yamagishi, C., Hierck, B. P., Gittenberger-De Groot, A. C., Yamagishi, H., Srivastava, D. Functional attenuation of Ufd1l, a 22q11.2 deletion syndrome candidate gene, leads to cardiac outflow septation defects in chicken embryos. Pediat. Res. 53: 546-553, 2003. [PubMed: 12612215] [Full Text: https://doi.org/10.1203/01.PDR.0000055765.11310.E3]
Yamagishi, H., Garg, V., Matsuoka, R., Thomas, T., Srivastava, D. A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Science 283: 1158-1161, 1999. [PubMed: 10024240] [Full Text: https://doi.org/10.1126/science.283.5405.1158]