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Oxford Medical Case Reports Dec 2015Mulibrey (MUscle-LIver-BRain-EYe) nanism is a rare autosomal recessive disease characterized by growth failure, dysmorphic features and a wide range of abnormalities...
Mulibrey (MUscle-LIver-BRain-EYe) nanism is a rare autosomal recessive disease characterized by growth failure, dysmorphic features and a wide range of abnormalities affecting multiple organ systems. This report is the first to present two cases of Mulibrey nanism affecting two siblings from Syria. Mulibrey nanism can be suspected clinically due to the distinctive features of the patients. The aim of this report is to document the presence of Mulibrey nanism in Syria and to familiarize physicians in and out of Syria with this rare disease and encourage them to develop high clinical suspicion if faced with patients with similar presentations.
PubMed: 26664725
DOI: 10.1093/omcr/omv065 -
Journal of Investigative Medicine High... 2022Mulibrey (scle-er-ain-e) Nanism syndrome is an extremely rare genetic disorder with multiorgan involvement. Constrictive pericarditis and diastolic dysfunction are the...
Mulibrey (scle-er-ain-e) Nanism syndrome is an extremely rare genetic disorder with multiorgan involvement. Constrictive pericarditis and diastolic dysfunction are the most common causes of mortality. We present a case of a patient with Mulibrey nanism syndrome who underwent pericardiectomy at 12 years old and was able to live 44 years more with relatively stable and asymptomatic diastolic congestive heart failure (CHF). This case highlights the importance of early recognition and treatment of constrictive pericarditis in these patients.
Topics: Child; Humans; Mulibrey Nanism; Pericardiectomy; Pericarditis, Constrictive
PubMed: 35257621
DOI: 10.1177/23247096221077816 -
Biology Open May 2016Mulibrey nanism (MUL) is a rare autosomal recessive multi-organ disorder characterized by severe prenatal-onset growth failure, infertility, cardiopathy, risk for...
Mulibrey nanism (MUL) is a rare autosomal recessive multi-organ disorder characterized by severe prenatal-onset growth failure, infertility, cardiopathy, risk for tumors, fatty liver, and type 2 diabetes. MUL is caused by loss-of-function mutations in TRIM37, which encodes an E3 ubiquitin ligase belonging to the tripartite motif (TRIM) protein family and having both peroxisomal and nuclear localization. We describe a congenic Trim37 knock-out mouse (Trim37(-/-)) model for MUL. Trim37(-/-) mice were viable and had normal weight development until approximately 12 months of age, after which they started to manifest increasing problems in wellbeing and weight loss. Assessment of skeletal parameters with computer tomography revealed significantly smaller skull size, but no difference in the lengths of long bones in Trim37(-/-) mice as compared with wild-type. Both male and female Trim37(-/-) mice were infertile, the gonads showing germ cell aplasia, hilus and Leydig cell hyperplasia and accumulation of lipids in and around Leydig cells. Male Trim37(-/-) mice had elevated levels of follicle-stimulating and luteinizing hormones, but maintained normal levels of testosterone. Six-month-old Trim37(-/-) mice had elevated fasting blood glucose and low fasting serum insulin levels. At 1.5 years Trim37(-/-) mice showed non-compaction cardiomyopathy, hepatomegaly, fatty liver and various tumors. The amount and morphology of liver peroxisomes seemed normal in Trim37(-/-) mice. The most consistently seen phenotypes in Trim37(-/-) mice were infertility and the associated hormonal findings, whereas there was more variability in the other phenotypes observed. Trim37(-/-) mice recapitulate several features of the human MUL disease and thus provide a good model to study disease pathogenesis related to TRIM37 deficiency, including infertility, non-alcoholic fatty liver disease, cardiomyopathy and tumorigenesis.
PubMed: 27044324
DOI: 10.1242/bio.016246 -
ELife Jan 2021TRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease with impaired organ growth and increased tumor formation. TRIM37 depletion from tissue culture...
TRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease with impaired organ growth and increased tumor formation. TRIM37 depletion from tissue culture cells results in supernumerary foci bearing the centriolar protein Centrin. Here, we characterize these centriolar protein assemblies (Cenpas) to uncover the mechanism of action of TRIM37. We find that an atypical de novo assembly pathway can generate Cenpas that act as microtubule-organizing centers (MTOCs), including in Mulibrey patient cells. Correlative light electron microscopy reveals that Cenpas are centriole-related or electron-dense structures with stripes. TRIM37 regulates the stability and solubility of Centrobin, which accumulates in elongated entities resembling the striped electron dense structures upon TRIM37 depletion. Furthermore, Cenpas formation upon TRIM37 depletion requires PLK4, as well as two parallel pathways relying respectively on Centrobin and PLK1. Overall, our work uncovers how TRIM37 prevents Cenpas formation, which would otherwise threaten genome integrity.
Topics: Cell Cycle Proteins; Cell Line; Centrioles; HeLa Cells; Humans; Microtubule-Organizing Center; Mulibrey Nanism; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 33491649
DOI: 10.7554/eLife.62640 -
Autophagy 2018TRIM37 gene mutations cause mulibrey (muscle-liver-brain-eye) nanism, a severe growth disorder with prenatal onset. Although TRIM37 depletion normally induces apoptosis,...
UNLABELLED
TRIM37 gene mutations cause mulibrey (muscle-liver-brain-eye) nanism, a severe growth disorder with prenatal onset. Although TRIM37 depletion normally induces apoptosis, patients with TRIM37 mutations have a high risk of developing tumors, suggesting that there may be an alternative pro-survival mechanism for TRIM37-deficient tumor cells. We find that TRIM37 interacts with MTOR and RRAGB proteins, enhances the MTOR-RRAGB interaction and promotes lysosomal localization of MTOR, thereby activating amino acid-stimulated MTORC1 signaling. In response to loss of TRIM37 functions, phosphorylation of TFEB is significantly reduced, resulting in its translocation into the nucleus enabling its transcriptional activation of genes involved in lysosome biogenesis and macroautophagy/autophagy. The enhanced autophagy depends on the inhibition of MTORC1 signaling and may serve as an alternative mechanism to survive the loss of TRIM37 functions. Our study unveils a positive role of TRIM37 in regulating the MTORC1-TFEB axis and provides mechanistic insights into the pathogenesis of mulibrey nanism, as well as potential therapeutic treatment.
ABBREVIATIONS
ACTB: actin beta; ATG: autophagy related; CASP3: caspase3; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; CTS: cathepsin proteases; CTSL: cathepsin L; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LMNB1: lamin B1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; mulibrey: muscle-liver-brain-eye; NAC: N-acetyl-L-cysteine; PARP1: poly(ADP-ribose) polymerase 1; RAP2A: member of RAS oncogene family; RHEB: Ras homolog enriched in brain; ROS: reactive oxygen species; RPS6KB1: ribosomal protein S6 kinase B1; RRAGB: Ras related GTP binding B; SQSTM1: sequestosome 1; TFEB: transcription factor EB; TRIM37: tripartite motif containing 37.
Topics: Amino Acids; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Nucleus; Cell Survival; HEK293 Cells; Hep G2 Cells; Humans; Lysosomes; Mechanistic Target of Rapamycin Complex 1; Monomeric GTP-Binding Proteins; Nuclear Proteins; Phosphorylation; Protein Binding; Protein Transport; Signal Transduction; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 29940807
DOI: 10.1080/15548627.2018.1463120 -
American Journal of Human Genetics May 2002Mulibrey nanism is a rare growth disorder of prenatal onset caused by mutations in the TRIM37 gene, which encodes a RING-B-box-coiled-coil protein. The pathogenetic...
Mulibrey nanism is a rare growth disorder of prenatal onset caused by mutations in the TRIM37 gene, which encodes a RING-B-box-coiled-coil protein. The pathogenetic mechanisms of mulibrey nanism are unknown. We have used transiently transfected cells and antibodies raised against the predicted TRIM37 protein to characterize the TRIM37 gene product and to determine its intracellular localization. We show that the human TRIM37 cDNA encodes a peroxisomal protein with an apparent molecular weight of 130 kD. Peroxisomal localization is compromised in mutant protein representing the major Finnish TRIM37 mutation but is retained in the protein representing the minor Finnish mutation. Colocalization of endogenous TRIM37 with peroxisomal markers was observed by double immunofluorescence staining in HepG2 and human intestinal smooth muscle cell lines. In human tissue sections, TRIM37 shows a granular cytoplasmic pattern. Endogenous TRIM37 is not imported into peroxisomes in peroxin 1 (PEX1(-/-)) and peroxin 5 (PEX5(-/-)) mutant fibroblasts but is imported normally in peroxin 7 (PEX7(-/-)) deficient fibroblasts, giving further evidence for a peroxisomal localization of TRIM37. Fibroblasts derived from patients with mulibrey nanism lack C-terminal TRIM37 immunoreactivity but stain normally for both peroxisomal matrix and membrane markers, suggesting apparently normal peroxisome biogenesis in patient fibroblasts. Taken together, this molecular evidence unequivocally indicates that TRIM37 is located in the peroxisomes, and Mulibrey nanism thus can be classified as a new peroxisomal disorder.
Topics: ATPases Associated with Diverse Cellular Activities; Amino Acid Motifs; Animals; Antibodies; Blotting, Western; Cell Line; Cricetinae; Dwarfism; Fibroblasts; Finland; Gene Expression Profiling; Glycoproteins; Humans; Immunohistochemistry; Membrane Proteins; Molecular Weight; Mutation; Nuclear Proteins; Peroxisomal Disorders; Peroxisomal Targeting Signal 2 Receptor; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Protein Biosynthesis; Protein Structure, Tertiary; Protein Transport; Proteins; Receptors, Cytoplasmic and Nuclear; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 11938494
DOI: 10.1086/340256 -
American Journal of Human Genetics Apr 1997Mulibrey nanism (MUL) is an autosomal recessive disorder with unknown basic metabolic defect. It is characterized by growth failure of prenatal onset, characteristic...
Mulibrey nanism (MUL) is an autosomal recessive disorder with unknown basic metabolic defect. It is characterized by growth failure of prenatal onset, characteristic dysmorphic features, constrictive pericardium, hepatomegaly as a consequence of constrictive pericardium, yellowish dots in the ocular fundi, and J-shaped sella turcica. Hypoplasia of various endocrine glands, causing hormone deficiencies, is common. Here we report the assignment of the MUL gene, by linkage analysis in Finnish families, to a 7-cM region flanked by D17S1799 and D17S948 on chromosome 17q. Multipoint linkage analysis gave a maximum LOD score of 5.01 at loci D17S1606-D17S1853 and at D17S1604. The estimate of the critical MUL region was further narrowed to within approximately 250 kb of marker D17S1853 by linkage disequilibrium analysis. Positional candidate genes that belong to the growth hormone and homeobox B gene clusters were excluded. These data confirm the autosomal recessive inheritance of MUL and allow highly focused attempts to clone the gene.
Topics: Abnormalities, Multiple; Brain; Chromosome Mapping; Chromosomes, Human, Pair 17; Dwarfism; Eye Abnormalities; Female; Finland; Genes, Recessive; Genetic Markers; Homeodomain Proteins; Humans; Linkage Disequilibrium; Liver; Lod Score; Male; Microsatellite Repeats; Muscles; Polymorphism, Genetic; Recombination, Genetic
PubMed: 9106536
DOI: No ID Found -
Genome Research Mar 1999Previously, we assigned the genes for two autosomal recessive disorders, Meckel syndrome (MKS; MIM 249000) and Mulibrey Nanism [MUL (muscle-liver-brain-eye Nanism); MIM...
Previously, we assigned the genes for two autosomal recessive disorders, Meckel syndrome (MKS; MIM 249000) and Mulibrey Nanism [MUL (muscle-liver-brain-eye Nanism); MIM 253250] that are enriched in the Finnish population, to overlapping genomic regions on chromosome 17q. Now, we report the construction of a bacterial clone contig over the critical region for both disorders. Several novel CA-repeat markers were isolated from these clones, which allowed refined mapping of the MKS and MUL loci using haplotype and linkage disequilibrium analysis. The localization of the MKS locus was narrowed to <1 cM between markers D17S1290 and 132-CA, within an approximately 800-kb region. The MUL locus was refined into an approximately 1400-kb interval between markers D17S1290 and 52-CA. The whole MKS region falls within the MUL region. In the common critical region, the conserved haplotypes were different in MKS and MUL patients. A trancript map was constructed by assigning expressed sequence tags (ESTs) and genes, derived from the human gene map, to the bacterial clone contig. Altogether, four genes and a total of 20 ESTs were precisely localized. These data provide the molecular tools for the final identification of the MKS and the MUL genes.
Topics: Chromosome Mapping; Chromosomes, Human, Pair 17; DNA-Binding Proteins; Dwarfism; Encephalocele; Genes, Recessive; Humans; Linkage Disequilibrium; Meningocele; Molecular Sequence Data; Physical Chromosome Mapping; Polycystic Kidney, Autosomal Recessive; Polydactyly; Syndrome; T-Box Domain Proteins
PubMed: 10077533
DOI: No ID Found -
Iranian Journal of Public Health Dec 2022Mulibrey Nanism is a rare multisystem disorder inherited in an autosomal recessive manner caused by mutations in the gene. Most of the reported cases are from Finland,...
Mulibrey Nanism is a rare multisystem disorder inherited in an autosomal recessive manner caused by mutations in the gene. Most of the reported cases are from Finland, but this condition has rarely occurred in other countries. Although the clinical diagnosis of Mulibrey nanism is a challenge during the first months of life, the disease can be suspected clinically due to the distinctive features of the patients. A 4-year-old female with pneumonia, cardiomyopathy, growth retardation, peripheral edema, and characteristic craniofacial features was referred to Tehran Hope Generation Foundation Genetic diagnosis Center, in October 2021. Genomic DNA was isolated from peripheral blood samples of the patient and her parents and Whole exome sequencing was performed for the patient. Whole exome sequencing revealed a homozygous G>A splice site variant (; c.370-1G>A). Sanger sequencing confirmed the segregation of the variant with phenotype in this family. Whole exome sequencing can be helpful in the diagnosis of the patients suspecting to Mulibrey nanism and lacking sufficient clinical presentation according to the diagnostic algorithm.
PubMed: 36742244
DOI: 10.18502/ijph.v51i12.11474 -
The Journal of Cell Biology Sep 2017Most proteins destined for the peroxisomal matrix depend on the peroxisomal targeting signals (PTSs), which require the PTS receptor PEX5, whose deficiency causes fatal...
Most proteins destined for the peroxisomal matrix depend on the peroxisomal targeting signals (PTSs), which require the PTS receptor PEX5, whose deficiency causes fatal human peroxisomal biogenesis disorders (PBDs). gene mutations cause muscle-liver-brain-eye (mulibrey) nanism. We found that TRIM37 localizes in peroxisomal membranes and ubiquitylates PEX5 at K464 by interacting with its C-terminal 51 amino acids (CT51), which is required for PTS protein import. PEX5 mutations (K464A or ΔCT51), or TRIM37 depletion or mutation, reduce PEX5 abundance by promoting its proteasomal degradation, thereby impairing its functions in cargo binding and PTS protein import in human cells. TRIM37 or PEX5 depletion induces apoptosis and enhances sensitivity to oxidative stress, underscoring the cellular requirement for functional peroxisomes. Therefore, TRIM37-mediated ubiquitylation stabilizes PEX5 and promotes peroxisomal matrix protein import, suggesting that mulibrey nanism is a new PBD.
Topics: Animals; Apoptosis; Genetic Predisposition to Disease; HEK293 Cells; Hep G2 Cells; Humans; Mice; Mulibrey Nanism; Mutation; Nuclear Proteins; Organelle Biogenesis; Oxidative Stress; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Phenotype; Proteasome Endopeptidase Complex; Protein Binding; Protein Interaction Domains and Motifs; Protein Stability; Protein Transport; Proteolysis; RAW 264.7 Cells; Receptors, Cytoplasmic and Nuclear; Time Factors; Transfection; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 28724525
DOI: 10.1083/jcb.201611170