Alternative titles; symbols
HGNC Approved Gene Symbol: FBXO11
Cytogenetic location: 2p16.3 Genomic coordinates (GRCh38) : 2:47,806,920-47,906,498 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p16.3 | Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities | 618089 | Autosomal dominant | 3 |
F-box proteins, such as FBXO11, contain an approximately 40-amino acid motif, the F box, that binds SKP1 (601434). Some F-box proteins control the degradation of cellular regulatory proteins as 1 of 4 subunits, along with SKP1, cullin (see 603134), and ROC1 (RBX1; 603814) of SCF ubiquitin protein ligases (Cenciarelli et al., 1999). FBXO11 is downregulated in vitiligo (606579), a disorder that presents with progressive skin depigmentation (Le Poole et al., 2001).
By differential expression analysis, Le Poole et al. (2001) identified a fragment of FBXO11, which they called VIT1, by its absence in melanocytes cultured from generalized vitiligo patients compared with normal control cells. By screening a melanocyte cDNA library with the fragment, they cloned full-length FBXO11. The deduced 141-amino acid protein has a calculated molecular mass of about 14 kD. Le Poole et al. (2001) isolated a second clone, which may be a splice variant encoding an FBXO11 protein truncated at 34 amino acids, from the melanocyte cDNA library. FBXO11 contains a zinc finger motif that shares 45% identity with the N-recognin (605981) zinc finger motif. RT-PCR detected expression in keratinocytes, fibroblasts, and melanocytes. Expression was not detected by Northern blot analysis, suggesting low expression levels.
Jin et al. (2004) reported that the FBXO11 protein contains an F box in its N-terminal half and 2 tandem CASH domains, which are found in carbohydrate-binding proteins and sugar hydrolases, in its C-terminal half.
Cook et al. (2006) reported that alternative splicing of FBXO11, which they called PRMT9, produces 4 protein isoforms. Isoform-1 contains 843 residues and has an N-terminal F-box domain, 4 central putative protein arginine methyltransferase (PRMT) motifs, and a C-terminal zinc finger motif. Isoform-2 and isoform-3 contain 686 and 585 residues, respectively, and lack the C-terminal zinc finger motif. Isoform-4 contains 561 residues and lacks both the N-terminal F-box and C-terminal zinc finger motif. PRMT9 shares limited sequence homology and primary structure with other human PRMTs, but orthologs of PRMT9 are found in vertebrates to unicellular eukaryotes and archaebacteria. Epitope-tagged PRMT9 isoform-4 was detected in the cytoplasm and nucleus of transfected COS cells.
By PCR of HeLa cell cDNA, followed by 5-prime RACE and database analysis, Abida et al. (2007) cloned full-length FBXO11. The 927-amino acid protein contains an N-terminal F-box, 3 central CASH domains, and a C-terminal zinc finger-like UBR box.
Le Poole et al. (2001) determined that the FBXO11 gene contains 4 potential exons and spans about 5 kb.
By genomic sequence analysis, Le Poole et al. (2001) mapped the FBXO11 gene to chromosome 2p16. Jin et al. (2004) stated that the FBXO11 gene maps to chromosome 2p21 and the mouse Fbxo11 gene maps to chromosome 17E5.0.
Wolf (2009) reported that the FBXO11 gene maps to chromosome 2p16.3.
Le Poole et al. (2001) determined that the 3-prime terminus of FBXO11 is complementary to the 3-prime terminus of the MSH6 gene (600678). MSH6 is a G/T mismatch repair enzyme that also maps to chromosome 2p16. Le Poole et al. (2001) determined that the decreased levels of FBXO11 in vitiligo cells were associated with increased levels of MSH6. They noted that double-stranded RNA can mediate posttranscriptional gene silencing and hypothesized that FBXO11 may modulate MSH6 expression.
Using human PRMT9 isoform-4 immunopurified from transfected HeLa cells or recombinant isoform-4 isolated from E. coli, Cook et al. (2006) found that PRMT9 showed methyltransferase activity against several protein and peptide substrates that contained arginines, but not against peptides that lacked arginines. All methylated substrates contained monomethylated arginine and symmetrically dimethylated arginines. Smaller amounts of asymmetrically dimethylated arginines were also observed with most substrates.
Abida et al. (2007) found that FBXO11 coprecipitated with p53 (TP53; 191170) from H1299 human lung carcinoma cells as a major band of about 120 kD. Endogenous p53 and FBXO11 coimmunoprecipitated from HCT116 human colorectal carcinoma cells. FBXO11 also coimmunoprecipitated with the SCF ubiquitin ligase complex. FBXO11 did not promote p53 ubiquitination and degradation, but it promoted p53 neddylation (see NEDD8, 603171). Conjugation of NEDD8 to p53 was lost with deletion of the F-box domain of FBXO11, or when 8 lysines of p53, including lys320 and lys321 within a nuclear localization signal, were mutated to arginine. Knockdown of FBXO11 in U2OS cells resulted in enhanced levels of p21 (CDKN1A; 116899), a primary p53 transcriptional target. Abida et al. (2007) concluded that full-length FBXO11 functions within the SCF complex in p53 neddylation, inhibiting p53 transcriptional activity.
Intellectual Developmental Disorder with Dysmorphic Facies and Behavioral Abnormalities
In 18 unrelated patients with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA; 618089), Gregor et al. (2018) reported de novo heterozygous mutations in the FBXO11 gene (see, e.g., 607871.0001-607871.0005). The patients were identified through collaborative efforts of research groups with exome sequencing data from patients with developmental delay. There were 10 nonsense, splice site, or frameshift mutations (likely gene-disrupting, LGD) and 8 missense mutations at highly conserved residues distributed throughout the gene. Two additional patients carried larger deletions, including 1 patient with deletion of additional genes. None of the variants were present in the ExAC or gnomAD databases. Functional studies of the variants and studies of patient cells were not performed, but the presence of LGDs and molecular modeling of the missense mutations predicted that all would result in a loss of function and haploinsufficiency. One of the patients (patient 18) was originally reported by Martinez et al. (2017) as part of a large study of 92 patients with intellectual disability who underwent next-generation sequencing of a gene panel.
Fritzen et al. (2018) reported 2 unrelated patients with IDDFBA associated with de novo heterozygous mutations in the FBXO11 gene (607871.0005 and 607871.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but both were predicted to result in a loss of function.
Jansen et al. (2019) identified 24 individuals with impaired intellectual development with behavior problems and dysmorphic features who had heterozygosity for a de novo variant in or partial deletion of the FBXO11 gene. Among these 24 individuals, 22 variants were identified by next-generation sequencing, including 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to premature termination or degraded transcript. The remaining 2 variants were identified using chromosome microarray and consisted of partial deletions of FBXO11: a 21-kb intragenic deletion of exons 2-13, and a 170-kb deletion disrupting the 3-prime end of FBXO11 by deleting exons 12-24.
Somatic Mutations in Diffuse Large B Cell Lymphoma
Duan et al. (2012) demonstrated that BCL6 (109565) is targeted for ubiquitylation and proteasomal degradation by a SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complex that contains the F-box protein FBXO11. The gene encoding FBXO11 was found to be deleted or mutated in multiple diffuse large B-cell lymphoma (DLBCL) cell lines, and this inactivation of FBXO11 correlated with increased levels and stability of BCL6. Similarly, FBXO11 was either deleted or mutated in primary DLBCLs. Notably, tumor-derived FBXO11 mutants displayed an impaired ability to induce BCL6 degradation. Reconstitution of FBXO11 expression in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited cell proliferation, and induced cell death. FBXO11-deleted DLBCL cells generated tumors in immunodeficient mice, and the tumorigenicity was suppressed by FBXO11 reconstitution. Duan et al. (2012) revealed a molecular mechanism controlling BCL6 stability and proposed that mutations and deletions in FBXO11 contribute to lymphomagenesis through BCL6 stabilization. The authors stated that deletions/mutations found in DLBCLs are largely monoallelic, indicating that FBXO11 is a haploinsufficient tumor suppressor gene.
In a 9-year-old boy (patient 1) with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA; 618089), Gregor et al. (2018) identified a de novo heterozygous c.1612A-G transition (c.1612A-G, NM_001190274.1) in the FBXO11 gene, resulting in an ile538-to-val (I538V) substitution at a highly conserved residue in the first CASH domain, which is important for substrate recognition. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling suggested that the variant would destabilize the CASH domain, resulting in a loss of function and haploinsufficiency.
In an 8-year-old girl (patient 2) with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA; 618089), Gregor et al. (2018) identified a de novo heterozygous c.414A-T transversion (c.414A-T, NM_001190274.1) in the FBXO11 gene, resulting in an arg138-to-ser (R138S) substitution at a highly conserved residue upstream of the F-Box like domain. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function and haploinsufficiency.
In a 29-year-old woman (patient 5) with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA; 618089), Gregor et al. (2018) identified a de novo heterozygous c.2518T-C transition (c.2518T-C, NM_001190274.1) in the FBXO11 gene, resulting in a ser840-to-pro (S840P) substitution at a highly conserved residue in the UBR-domain, which is important for E3 ubiquitin ligase function. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutations would result in a loss of function and haploinsufficiency.
In a 2-year-old boy (patient 17) with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA; 618089), Gregor et al. (2018) identified a de novo heterozygous 1-bp duplication (c.2709dup, NM_001190274.1) in the FBXO11 gene, predicted to result in a frameshift and premature termination (Glu904Ter).
In a 9-year-old boy (patient 18) with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA; 618089), Gregor et al. (2018) identified a de novo heterozygous 2-bp deletion (c.2738_2739delAT, NM_001190274.1) in the FBXO11 gene, predicted to result in a frameshift and premature termination (Tyr913Ter). Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function with haploinsufficiency. The patient was originally reported by Martinez et al. (2017) as part of a large study of 92 patients with intellectual disability who underwent next-generation sequencing of a gene panel.
In a 3-year-old boy with IDDFBA, Fritzen et al. (2018) identified a de novo heterozygous c.2738_2739delAT mutation in exon 23 of the FBXO11 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
In a 14-year-old German boy (patient 1) with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA; 618089), Fritzen et al. (2018) identified a de novo heterozygous 1-bp duplication (c.442+1dup, NM_001190274) in intron 3 of the FBXO11 gene, predicted to result in aberrant splicing and a loss of function. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. It was not present in the dbSNP or ExAC databases. Functional studies of the variants and studies of patient cells were not performed, but it was predicted to result in a loss of function.
Abida, W. M., Nikolaev, A., Zhao, W., Zhang, W., Gu, W. FBXO11 promotes the neddylation of p53 and inhibits its transcriptional activity. J. Biol. Chem. 282: 1797-1804, 2007. [PubMed: 17098746] [Full Text: https://doi.org/10.1074/jbc.M609001200]
Cenciarelli, C., Chiaur, D. S., Guardavaccaro, D., Parks, W., Vidal, M., Pagano, M. Identification of a family of human F box proteins. Curr. Biol. 9: 1177-1179, 1999. [PubMed: 10531035] [Full Text: https://doi.org/10.1016/S0960-9822(00)80020-2]
Cook, J. R., Lee, J.-H., Yang, Z.-H., Krause, C. D., Herth, N., Hoffmann, R., Pestka, S. FBXO11/PRMT9, a new protein arginine methyltransferase, symmetrically dimethylates arginine residues. Biochem. Biophys. Res. Commun. 342: 472-481, 2006. [PubMed: 16487488] [Full Text: https://doi.org/10.1016/j.bbrc.2006.01.167]
Duan, S., Cermak, L., Pagan, J. K., Rossi, M., Martinengo, C., Francia di Celle, P., Chapuy, B., Shipp, M., Chiarle, R., Pagano, M. FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature 481: 90-93, 2012. [PubMed: 22113614] [Full Text: https://doi.org/10.1038/nature10688]
Fritzen, D., Kuechler, A., Grimmel, M., Becker, J., Peters, S., Sturm, M., Hundertmark, H., Schmidt, A., Kreiss, M., Strom, T. M., Wieczorek, D., Haack, T. B., Beck-Wodl, S., Cremer, K., Engels, H. De novo FBXO11 mutations are associated with intellectual disability and behavioural anomalies. Hum. Genet. 137: 401-411, 2018. [PubMed: 29796876] [Full Text: https://doi.org/10.1007/s00439-018-1892-1]
Gregor, A., Sadleir, L. G., Asadollahi, R., Azzarello-Burri, S., Battaglia, A., Ousager, L. B., Boonsawat P., Bruel, A.-L., Buchert, R., Calpena, E., Cogne, B., Dallapiccola, B., and 38 others. De novo variants in the F-box protein FBXO11 in 20 individuals with a variable neurodevelopmental disorder. Am. J. Hum. Genet. 103: 305-316, 2018. [PubMed: 30057029] [Full Text: https://doi.org/10.1016/j.ajhg.2018.07.003]
Jansen, S., van der Werf, I. M., Innes, A. M., Afenjar, A., Agrawal, P. B., Anderson, I. J., Atwal, P. S., van Binsbergen, E., van den Boogaard, M.-J., Castiglia, L., Coban-Akdemir, Z. H., van Dijck, A., and 39 others. De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms. Europ. J. Hum. Genet. 27: 738-746, 2019. [PubMed: 30679813] [Full Text: https://doi.org/10.1038/s41431-018-0292-2]
Jin, J., Cardozo, T., Lovering, R. C., Elledge, S. J., Pagano, M., Harper, J. W. Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev. 18: 2573-2580, 2004. [PubMed: 15520277] [Full Text: https://doi.org/10.1101/gad.1255304]
Le Poole, I. C., Sarangarajan, R., Zhao, Y., Stennett, L. S., Brown, T. L., Sheth, P., Miki, T., Boissy, R. E. 'VIT1', a novel gene associated with vitiligo. Pigment Cell Res. 14: 475-484, 2001. [PubMed: 11775060] [Full Text: https://doi.org/10.1034/j.1600-0749.2001.140608.x]
Martinez, F., Caro-Llopis, A., Rosello, M., Oltra, S., Mayo, S., Monfort, S., Orellana, C. High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. J. Med. Genet. 54: 87-92, 2017. [PubMed: 27620904] [Full Text: https://doi.org/10.1136/jmedgenet-2016-103964]
Wolf, S. S. The protein arginine methyltransferase family: an update about function, new perspectives and the physiological role in humans. Cell. Molec. Life Sci. 66: 2109-2121, 2009. [PubMed: 19300908] [Full Text: https://doi.org/10.1007/s00018-009-0010-x]