Mutations in MAFB that cause Multicentric Carpo Tarsal Osteolysis (MCTO) affect the transcriptome of M-MØ
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ABSTRACT:
PROVIDER: PRJNA655923 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12413845.fastq.gz | Fastqsanger.gz | |||
| SRR12413846.fastq.gz | Fastqsanger.gz | |||
| SRR12413847.fastq.gz | Fastqsanger.gz | |||
| SRR12413848.fastq.gz | Fastqsanger.gz |
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Project description:Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. Most studies addressing the molecular basis for macrophage heterogeneity have focused on murine cells, while the factors controlling the functional specialization of human macrophages are less known. M-CSF drives the generation of human monocyte-derived macrophages with a potent anti-inflammatory activity upon stimulation. The contribution of MAFB to the homeostatic/anti-inflammatory macrophage profile is further supported by the skewed polarization of monocyte-derived macrophages from Multicentric Carpo Tarsal Osteolysis (OMIM#166300), a pathology caused by mutations in the MAFB gene.
2023-07-14 | GSE155883 | GEO
Project description:Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. Most studies addressing the molecular basis for macrophage heterogeneity have focused on murine cells, while the factors controlling the functional specialization of human macrophages are less known. M-CSF drives the generation of human monocyte-derived macrophages with a potent anti-inflammatory activity upon stimulation. We now report that knock-down of MAFB impairs the acquisition of the anti-inflammatory profile of human macrophages, identify the MAFB-dependent gene signature in human macrophages and illustrate the co-expression of MAFB and MAFB-target genes in CD163+ tissue-resident and tumor associated macrophages. The contribution of MAFB to the homeostatic/anti-inflammatory macrophage profile is further supported by the skewed polarization of monocyte-derived macrophages from Multicentric Carpo Tarsal Osteolysis (OMIM#166300), a pathology caused by mutations in the MAFB gene. Our results demonstrate that MAFB critically determines the acquisition of the anti-inflammatory transcriptional and functional profiles of human macrophages.
2019-05-03 | GSE84616 | GEO
Project description:Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. Most studies addressing the molecular basis for macrophage heterogeneity have focused on murine cells, while the factors controlling the functional specialization of human macrophages are less known. M-CSF drives the generation of human monocyte-derived macrophages with a potent anti-inflammatory activity upon stimulation. We now report that knock-down of MAFB impairs the acquisition of the anti-inflammatory profile of human macrophages, identify the MAFB-dependent gene signature in human macrophages and illustrate the co-expression of MAFB and MAFB-target genes in CD163+ tissue-resident and tumor associated macrophages. The contribution of MAFB to the homeostatic/anti-inflammatory macrophage profile is further supported by the skewed polarization of monocyte-derived macrophages from Multicentric Carpo Tarsal Osteolysis (OMIM#166300), a pathology caused by mutations in the MAFB gene. Our results demonstrate that MAFB critically determines the acquisition of the anti-inflammatory transcriptional and functional profiles of human macrophages.
2019-05-03 | GSE84617 | GEO
Project description:Multicentric carpotarsal osteolysis (MCTO) is an ultra-rare skeletal dysplasia characterized by aggressive osteolysis and in many patients, progressive renal failure. Previous work identified autosomal dominant missense mutations in the transactivation domain of the transcription factor MAFB as the cause of MCTO. Because the pathological mechanism resulting in MCTO is not clear, we used mice carrying the MCTO mutation (MafbMCTO/MCTO mice) to determine the role of MAFB. Using a cycloheximide chase assay in HEK293T cells, we found that the MCTO mutation resulted in reduced degradation and thus accumulation of recombinant MAFB protein. MafbMCTO/MCTO mice exhibited focal segmental glomerulosclerosis (FSGS) similar to what is observed in MCTO patients. To analyze the effect of the excessive presence of MAFB, we generated heterozygous MafbMCTO/- mice by crossing MafbMCTO/MCTO and Mafb+/- animals. Such MafbMCTO/- mice did not suffer albuminuria and exhibited histologically normal kidney appearance. The finding that MCTO mutation haploinsufficiency rescues animals from nephropathy is consistent with the mutation resulting in excess MAFB as the cause of disease. Next, we performed RNA-seq of the glomeruli from MafbMCTO/MCTO mice. We found marked up-regulation of the PI3K/AKT signaling pathway. Because receptor tyrosine kinases are PI3K/AKT activators, we administered the specific inhibitor imatinib to MafbMCTO/MCTO mice. This resulted in a significant reduction of urinary albumin relative to untreated animals. Taken together, these results suggest that excess MAFB and the activation of PI3K/AKT signaling induce nephropathy in MCTO. MAFB and/or PI3K/AKT signaling may therefore represent new treatment targets in MCTO patients.
2025-03-31 | GSE211843 | GEO
Project description:Mutations in MAFB that cause Multicentric Carpo Tarsal Osteolysis (MCTO) affect the transcriptome of M-MØ
| PRJNA330670 | ENA
Project description:Multicentric carpo-tarsal osteolysis syndrome (MCTO) is a rare skeletal disorder commonly caused by MAF bZIP transcription factor B (MAFB) mutation. Clinically, it is characterized by aggressive osteolysis, which mainly affects the carpal tarsal bones, and is frequently associated with progressive nephropathy. Since the painful swelling and motion limitation on the wrists and/or ankles of MCTO mimics those of juvenile idiopathic arthritis (JIA), very often, MCTO is misdiagnosed as JIA. Here, we report two MCTO patients initially diagnosed with JIA but showed no response to treatment: P1, with a medical history of more than 10 years, was presented with a typical triad of arthritis-osteolysis-nephropathy; while P2 showed oligoarthritis. Gene tests were then taken and revealed a novel mutation, p.P63Q, and a previously reported conversion, p.S54L, in the MAFB gene. We also summarized the clinical and genetic features of a cohort containing 49 genetically confirmed MCTO patients. All 51 gene-confirmed MCTO cases (49 identified from the literature plus two patients identified herein) developed the disease during childhood. The median delay in diagnosis was 3.83 years (0-35 years). All cases presented bony lesions, and two-thirds had secondary renal lesions (32/48; three unknown), half of which (16/32) progressed into renal failure. Almost two-thirds (34/51), 75% (38/51), and 71% (36/51) of patients had no record of eye problems, facial abnormalities, and other manifestations. Most were misdiagnosed as JIA but didn't respond to treatment. Based on our experience, we suggest that clinicians should comprehensively evaluate the involvement of multiple systems in JIA patients, especially the kidney and eyes. And for JIA patients who underwent more than 3-month treatment with Bio-DMARD, genetic tests are recommended when they show little/no clinical and imaging changes, their high disease activity remains, and their disease activity remission is <50%, especially when combined with a triad of arthritis-osteolysis-nephropathy.
| S-EPMC8554157 | biostudies-literature
Project description:Inhibition of MAFB and PI3K/AKT-signaling reveals a potential therapeutic strategy for multicentric carpotarsal osteolysis-associated nephropathy
| PRJNA872343 | ENA
Project description:Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by aggressive osteolysis associated with progressive nephropathy. The early clinical presentation can mimic polyarticular juvenile idiopathic arthritis. Since 2012, MAFB mutations have been discovered in all MCTO patients. Therefore, the early diagnosis can be made based on genetic confirmation. We report the clinical manifestation of mineral bone disease and the molecular genetic study of a Thai female adolescent with MCTO. She presented with end-stage renal disease, bilateral wrist and ankle joint deformities, and subtle facial dysmorphic features. We identified a heterozygous missense MAFB mutation at nucleotide 197 from C to G (NM_005461.4; c.197C>G), predicting the change of amino acid at codon 66 from serine to cysteine (p.Ser66Cys), and the mutation was absent in the parents, indicating a de novo mutation. This report confirms the previous link between MAFB mutation and MCTO. Her unexplained hypercalcemia after a regular dose of calcium and active vitamin D supported an important role of MafB in the negative regulation of RANKL-mediated osteoclast differentiation. Therefore, we would encourage the physicians who take care of MCTO patients to closely monitor serum calcium level and perform a genetic study as a part of the management and investigation.
| S-EPMC6164201 | biostudies-literature
Project description:Multicentric carpo-tarsal osteolysis (MCTO) is a rare osteolysis syndrome mainly involving carpal and tarsal bones usually presenting in early childhood. MCTO has autosomal dominant inheritance with heterozygous mutation in the MAFB gene. The skeletal disorder is often associated with chronic kidney disease. Data on clinical characterization and best treatment option of MCTO-associated nephropathy are scarce and mostly limited to case reports. With the aim to better define the phenotype and long-term outcomes of MCTO-associated nephropathy, we launched an online survey through the Workgroup for hereditary glomerulopathies of the European Rare Kidney Disease Network (ERKNet). Overall, we collected clinical and genetic data of 54 MCTO patients, of which 42 previously described and 12 new patients. We observed a high rate of kidney involvement (70%), early age of kidney disease onset, nephrotic-range proteinuria, and a kidney survival around of 40% at long-term follow-up. Our finding confirmed the heterogeneity of clinical manifestations and widen the spectrum of phenotypes resulting from MCTO-associated nephropathy. Furthermore, we report the first case of complete remission after treatment with cyclosporine A. We demonstrated that multidisciplinary care is essential for MCTO patients and early referral to nephrologists is therefore warranted to facilitate prompt treatment.
| S-EPMC9369440 | biostudies-literature
Project description:Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia characterized by aggressive osteolysis, particularly affecting the carpal and tarsal bones, and is frequently associated with progressive renal failure. Using exome capture and next-generation sequencing in five unrelated simplex cases of MCTO, we identified previously unreported missense mutations clustering within a 51 base pair region of the single exon of MAFB, validated by Sanger sequencing. A further six unrelated simplex cases with MCTO were also heterozygous for previously unreported mutations within this same region, as were affected members of two families with autosomal-dominant MCTO. MAFB encodes a transcription factor that negatively regulates RANKL-induced osteoclastogenesis and is essential for normal renal development. Identification of this gene paves the way for development of novel therapeutic approaches for this crippling disease and provides insight into normal bone and kidney development.
| S-EPMC3309183 | biostudies-literature