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Cell Discovery Aug 2023The Mulibrey (Muscle-liver-brain-eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure...
The Mulibrey (Muscle-liver-brain-eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FIN (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (T) cell development and antibody production. The effects of Trim37 on T cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of T cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.
PubMed: 37528081
DOI: 10.1038/s41421-023-00561-z -
Frontiers in Immunology 2023Mulibrey nanism (MUL) is a rare disorder caused by gene variants characterized by growth failure, dysmorphic features, congestive heart failure (CHF), and an increased... (Review)
Review
INTRODUCTION
Mulibrey nanism (MUL) is a rare disorder caused by gene variants characterized by growth failure, dysmorphic features, congestive heart failure (CHF), and an increased risk of Wilms' tumor. Although immune system impairment has been documented in MUL, the underlying mechanisms remain poorly understood.
METHODS
We present a case of MUL with progressive lymphopenia and review similar cases from the literature.
RESULTS
Our patient presented with prenatal onset growth restriction, characteristic dysmorphic features, and Wilms' tumor. She developed progressive lymphopenia starting at 10 years of age, leading to the initiation of intravenous immunoglobulin (IVIG) replacement therapy and infection prophylaxis. Genetic analysis detected a likely pathogenic variant on the maternal allele and copy number loss on the paternal allele in . Subsequently a cardiac magnetic resonance imaging was conducted revealing signs of pericardial constriction raising concerns for intestinal lymphatic losses. The cessation of IVIG therapy did not coincide with any increase in the rate of infections. The patient exhibited a distinct immunological profile, characterized by hypogammaglobulinemia, impaired antibody responses, and skewed T-cell subsets with an altered CD4+/CD8+ ratio, consistent with previous reports. Normal thymocyte development assessed by artificial thymic organoid platform ruled out an early hematopoietic intrinsic defect of T-cell development.
DISCUSSION
The immunological profile of MUL patients reported so far shares similarities with that described in protein-losing enteropathy secondary to CHF in Fontan circulation and primary intestinal lymphangiectasia. These similarities include hypogammaglobulinemia, significant T-cell deficiency with decreased CD4+ and CD8+ counts, altered CD4+/CD8+ ratios, and significantly modified CD4+ and CD8+ T-cell phenotypes toward effector and terminal differentiated T cells, accompanied by a loss of naïve CD45RA+ T lymphocytes. In MUL, CHF is a cardinal feature, occurring in a significant proportion of patients and influencing prognosis. Signs of CHF or constrictive pericarditis have been evident in the case reported here and in all cases of MUL with documented immune dysfunction reported so far. These observations raise intriguing connections between these conditions. However, further investigation is warranted to in-depth define the immunological defect, providing valuable insights into the pathophysiology and treatment strategies for this condition.
Topics: Female; Humans; Agammaglobulinemia; Heart Failure; Immunoglobulins, Intravenous; Kidney Neoplasms; Lymphopenia; Mulibrey Nanism; Mutation; Nuclear Proteins; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Wilms Tumor
PubMed: 38116000
DOI: 10.3389/fimmu.2023.1303251 -
Cell Cycle (Georgetown, Tex.) Dec 2021Loss of function mutations in the E3 ubiquitin ligase TRIM37 result in MULIBREY nanism, a disease characterized by impaired organ growth and a high propensity to develop... (Review)
Review
Loss of function mutations in the E3 ubiquitin ligase TRIM37 result in MULIBREY nanism, a disease characterized by impaired organ growth and a high propensity to develop different tumor types. Additionally, increased copy number of TRIM37 is a feature of some breast cancers and neuroblastomas. The molecular role played by TRIM37 in such loss and gain of function conditions has been a focus of research in the last decade, which led notably to the identification of critical roles of TRIM37 in centrosome biology. Specifically, deletion of TRIM37 results in the formation of aberrant centrosomal proteins assemblies, including Centrobin-PLK4 assemblies, which can act as extra MTOCs, thus resulting in defective chromosome segregation. Additionally, TRIM37 overexpression targets the centrosomal protein CEP192 for degradation, thereby preventing centrosome maturation and increasing the frequency of mitotic errors. Interestingly, increased TRIM37 protein levels sensitize cells to the PLK4 inhibitor centrinone. In this review, we cover the emerging roles of TRIM37 in centrosome biology and discuss how this knowledge may lead to new therapeutic strategies to target specific cancer cells.
Topics: Centrosome; Chromosomal Proteins, Non-Histone; Humans; Microtubule-Organizing Center; Mulibrey Nanism; Protein Serine-Threonine Kinases; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 34672905
DOI: 10.1080/15384101.2021.1988289 -
Liver International : Official Journal... Jun 2022Mulibrey nanism (MUL) is a multiorgan disease caused by recessive mutations in the TRIM37 gene. Chronic heart failure and hepatopathy are major determinants of prognosis...
BACKGROUND AND AIMS
Mulibrey nanism (MUL) is a multiorgan disease caused by recessive mutations in the TRIM37 gene. Chronic heart failure and hepatopathy are major determinants of prognosis in MUL patients, which prompted us to study liver biochemistry and pathology in a national cohort of MUL patients.
METHODS
Clinical, laboratory and imaging data were collected in a cross-sectional survey and retrospectively from hospital records. Liver histology and immunohistochemistry for 10 biomarkers were assessed.
RESULTS
Twenty-one MUL patients (age 1-51 years) with tumour suspicion showed moderate congestion, steatosis and fibrosis in liver biopsies and marginally elevated levels of serum GGT, AST, ALT and AST to platelet ratio index (APRI) in 20%-66%. Similarly, GGT, AST, ALT and APRI levels were moderately elevated in 12%-69% of 17 MUL patients prior to pericardiectomy. In a cross-sectional evaluation of 36 MUL outpatients, GGT, total bilirubin and galactose half-life (Gal½) correlated with age (r = 0.45, p = .017; r = 0.512, p = .007; r = 0.44, p = .03 respectively). The frequency of clearly abnormal serum values of 15 parameters analysed, however, was low even in patients with signs of restrictive cardiomyopathy. Transient elastography (TE) of the liver revealed elevated levels in 50% of patients with signs of heart failure and TE levels correlated with several biochemistry parameters. Biomarkers of fibrosis, sinusoidal capillarization and hepatocyte metaplasia showed increased expression in autopsy liver samples from 15 MUL patients.
CONCLUSION
Liver disease in MUL patients was characterized by sinusoidal dilatation, steatosis and fibrosis with individual progression to cirrhosis and moderate association of histology with cardiac function, liver biochemistry and elastography.
Topics: Adolescent; Adult; Biomarkers; Child; Child, Preschool; Cross-Sectional Studies; Elasticity Imaging Techniques; Humans; Infant; Middle Aged; Mulibrey Nanism; Mutation; Retrospective Studies; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Young Adult
PubMed: 35220664
DOI: 10.1111/liv.15213 -
Cancer Reports (Hoboken, N.J.) May 2022Mulibrey-Nanism (Muscle-liver-brain-eye Nanism = dwarfism; MUL) is a rare genetic syndrome. The underlying TRIM37 mutation predisposes these children to develop tumors... (Review)
Review
BACKGROUND
Mulibrey-Nanism (Muscle-liver-brain-eye Nanism = dwarfism; MUL) is a rare genetic syndrome. The underlying TRIM37 mutation predisposes these children to develop tumors frequently. In the largest published series of MUL, 8% patients were reported to develop Wilms tumor (WT). The published literature lacks data regarding the best treatment protocol and outcome of this cohort of children with WT and MUL. We report here a 2-year-old boy with WT and MUL and present a review of literature on WT in MUL.
CASE
Our patient had associated cardiac problems of atrial septal defect, atrial flutter and an episode of sudden cardiac arrest. We managed him successfully with chemotherapy, surgery and multi-speciality care. He is alive and in remission at follow-up of 6 months.
CONCLUSION
A total of 14 cases (including present case) of WT have been reported in MUL and treatment details were available for six cases. They were managed primarily with surgery, chemotherapy with/without radiotherapy, and all achieved remission. The outcome data is available only for two cases, one has been followed up till 15 years post treatment for WT and other is our patient.
Topics: Child; Child, Preschool; Humans; Kidney Neoplasms; Male; Mulibrey Nanism; Nuclear Proteins; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Wilms Tumor
PubMed: 34309235
DOI: 10.1002/cnr2.1512 -
CJC Open Jan 2022Mulibrey nanism (MUL) is a rare condition with profound growth delay. Congestive heart failure is a major determinant of prognosis. The aim was to delineate pericardial...
BACKGROUND
Mulibrey nanism (MUL) is a rare condition with profound growth delay. Congestive heart failure is a major determinant of prognosis. The aim was to delineate pericardial constriction and myocardial functional abnormalities in a pediatric MUL sample.
METHODS
A total of 23 MUL patients and 23 individually sex- and age-matched healthy control subjects were prospectively assessed in a cross-sectional study with echocardiography.
RESULTS
Clinical signs of heart failure were present in 7 MUL patients, with severe congestive heart failure in 2. Significant diastolic dysfunction, mainly related to constriction, was found in MUL patients without pericardiectomy (N = 18)-septal bounce, pronounced hepatic vein atrial reversal and right heart inflow-outflow variations, and decreased inferior vena cava collapse during respiration. The appearance of the pericardium was not different from that of control subjects. Longitudinal diastolic myocardial velocities were similar to those in control subjects, suggesting an absence of significant myocardial restriction. Right ventricular free wall longitudinal systolic strain and bilateral longitudinal myocardial systolic velocities were decreased in MUL patients, indicating mild biventricular systolic dysfunction. Myocardial motion abnormalities and persistent congestive heart failure were common (in 3 of 6) in MUL patients with a history of pericardiectomy. Cardiac dimensions were similar between MUL patients and control subjects when adjusting for body size, except for smaller biventricular volumes.
CONCLUSIONS
MUL disease presents with significant constriction-related diastolic dysfunction and mild bilateral systolic dysfunction. Constriction-restriction assessments during follow-up could be of benefit in decision-making regarding pericardiectomy in MUL disease. Myocardial abnormalities were prevalent among MUL patients who had undergone pericardiectomy and are consistent with progression of myocardial disease in a significant proportion of patients.
PubMed: 35072025
DOI: 10.1016/j.cjco.2021.08.012 -
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 -
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 -
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 -
Frontiers in Immunology 2020Mulibrey (muscle-liver-brain-eye) syndrome (MUL) is an autosomal recessive disorder caused by mutations in the () gene, encoding for TRIM37 a member of the TRIM E3...
Mulibrey (muscle-liver-brain-eye) syndrome (MUL) is an autosomal recessive disorder caused by mutations in the () gene, encoding for TRIM37 a member of the TRIM E3 ubiquitin ligase protein family. MUL patients are characterized by growth retardation, dysmorphic features, and a wide range of abnormalities affecting different organs. However, T-cell abnormalities have not been observed in MUL subjects, to date. Here we described the immunological features of a MUL child carrying recently identified mutations, a 17q22 deletion of maternal origin combined with a variant of paternal origin. Here we found quantitative and functional defects in CD4 T cells from this MUL case. Low levels of TRIM37 protein were specifically detected in CD4 T cells of MUL patient and associated with their altered proliferation and cytokine production. Of note, both CD4 and CD8 T lymphocytes of MUL child displayed an effector memory phenotype compared with healthy children. This clinical case research highlighted the possible role of TRIM37 in the control of immune cell number and function, especially in CD4 T cells. Finally, this study may contribute to the novel mechanistic studies aim of identifying, in depth, the role of the TRIM37 protein in the immune system.
Topics: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Child; Cytokines; Genetic Predisposition to Disease; Heredity; Humans; Immunologic Memory; Lymphocyte Activation; Male; Mulibrey Nanism; Mutation; Pedigree; Phenotype; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 33042106
DOI: 10.3389/fimmu.2020.01742