| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| P51114 | Domain | 4 | 50 | Note=Agenet-like 1;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00973 | Type=Deletion;Start=1;End=85 |
| P51114 | Domain | 63 | 115 | Note=Agenet-like 2;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00973 | Type=Deletion;Start=1;End=85 |
| P51114 | Region | 545 | 621 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=540;End=621 |
| P51114 | Compositional bias | 555 | 575 | Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=540;End=621 |
| P51114 | Compositional bias | 594 | 608 | Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=540;End=621 |
| UniProt-id | Site score | Size | D score | Volume | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/Acc | Residues |
| P51114-1 | 0.931 | 84 | 0.952 | 196.882 | 0.586 | 0.652 | 0.902 | 0.887 | 0.923 | 0.96 | 0.362 | 140,143,145,146,147,148,149,150,153,184,187,188,19
1,192,194,195,196,198,476,477,480
|
| P51114-2 | 1.03 | 174 | 1.082 | 411.257 | 0.574 | 0.678 | 0.848 | 0.677 | 0.813 | 0.832 | 0.831 | 294,295,298,299,302,303,306,307,310,350,353,354,35
7,358,361,362,365,368,410,411,412,414,415,416,418,
419,420,422,423
|
| P51114-3 | 1.036 | 103 | 1.08 | 341.971 | 0.569 | 0.699 | 0.955 | 0.906 | 0.858 | 1.057 | 0.54 | 210,213,214,217,218,221,222,225,265,268,269,272,27
3,331,332,334,335,337,338,339,340
|
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| FXR1 | 10888599 | The fragile X-related proteins FXR1P and FXR2P contain a functional nucleolar-targeting signal equivalent to the HIV-1 regulatory proteins. | Fragile X syndrome is caused by the absence of the fragile X mental-retardation protein (FMRP). FMRP and the fragile X-related proteins 1 and 2 (FXR1P and FXR2P) form a gene family with functional similarities, such as RNA binding, polyribosomal association and nucleocytoplasmic shuttling. In a previous study, we found that FMRP and FXR1P shuttle between cytoplasm and nucleoplasm, while FXR2P shuttles between cytoplasm and nucleolus. The nuclear and nucleolar-targeting properties of these proteins were investigated further. Here, we show that FXR2P contains in its C-terminal part, a stretch of basic amino acids 'RPQRRNRSRRRRFR' that resemble the nucleolar-targeting signal (NoS) of the viral protein Rev. This particular sequence is also present within exon 15 of the FXR1 gene. This exon undergoes alternative splicing and is therefore only present in some of the FXR1P isoforms. We investigated the intracellular distribution of various FXR1P isoforms with (iso-e and iso-f) and without (iso-d) the potential NoS in transfected COS cells treated with the nuclear export inhibitor leptomycin-B. Both iso-e and iso-f showed a nucleolar localization, as observed for FXR2P; iso-d was detected in the nucleo-plasm outside the nucleoli. Further, when a labelled 16-residue synthetic peptide corresponding to the NoS of FXR1P was added to human fibroblast cultures a clear nucleolar signal was observed. Based on these data we argue that the intranuclear distribution of FXR2P and FXR1P isoforms is very likely to be mediated by a similar NoS localized in their C-terminal region. This domain is absent in some FXR1P isoforms as well as in all FMRP isoforms, suggesting functional differences for this family of proteins, possibly related to RNA metabolism in different tissues. | D005600 | Fragile X Syndrome |
| FXR1 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D004392 | Dwarfism |
| FXR1 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D006130 | Growth Disorders |
| FXR1 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D009123 | Muscle Hypotonia |
Gene summary
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