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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 -
International Journal of Molecular... Dec 2018TRIpartite motif (TRIM) proteins are part of the largest subfamilies of E3 ligases that mediate the transfer of ubiquitin to substrate target proteins. In this review,... (Review)
Review
TRIpartite motif (TRIM) proteins are part of the largest subfamilies of E3 ligases that mediate the transfer of ubiquitin to substrate target proteins. In this review, we focus on TRIM37 in the normal cell and in pathological conditions, with an emphasis on the MULIBREY (MUscle-LIver-BRain-EYe) genetic disorder caused by mutations. TRIM37 is characterized by the presence of a RING domain, B-box motifs, and a coiled-coil region, and its C-terminal part includes the MATH domain specific to TRIM37. MULIBREY nanism is a rare autosomal recessive caused by mutations and characterized by severe pre- and postnatal growth failure. Constrictive pericarditis is the most serious anomaly of the disease and is present in about 20% of patients. The patients have a deregulation of glucose and lipid metabolism, including type 2 diabetes, fatty liver, and hypertension. Puzzlingly, MULIBREY patients, deficient for TRIM37, are plagued with numerous tumors. Among non-MULIBREY patients affected by cancer, a wide variety of cancers are associated with an overexpression of TRIM37. This suggests that normal cells need an optimal equilibrium in TRIM37 expression. Finding a way to keep that balance could lead to potential innovative drugs for MULIBREY nanism, including heart condition and carcinogenesis treatment.
Topics: Cardiovascular Diseases; Humans; Immunity, Innate; Inflammation; Mulibrey Nanism; NF-kappa B; Neoplasms; Nuclear Proteins; Polymorphism, Genetic; Tripartite Motif Proteins; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 30586926
DOI: 10.3390/ijms20010067 -
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 -
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 -
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 -
Modern Pathology : An Official Journal... Apr 2009Mulibrey nanism is an autosomal recessive growth disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function. More than half of female...
Mulibrey nanism is an autosomal recessive growth disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function. More than half of female patients with Mulibrey nanism develop benign mesenchymal tumors of ovarian sex cord-stromal origin. In this work, we characterize the gynecological tumors of female patients with Mulibrey nanism in detail. In addition to tumors of the fibrothecoma group, 18% (4/22) of the patients were observed with epithelial neoplasias, including 2 ovarian adenofibromas, 1 ovarian poorly differentiated adenocarcinoma and 1 endometrial adenocarcinoma. To investigate the possible involvement of TRIM37 alterations in the pathogenesis of sporadic fibrothecomas, we analyzed the TRIM37 cDNA for mutations and alternatively spliced transcripts and TRIM37 expression in fibrothecomas of women without Mulibrey nanism. No mutations in the open-reading frame of TRIM37 were detected. Two alternatively spliced variants were found, one lacking exon 23 and one exon 2. TRIM37del2 was also found in normal ovary but in a proportion of sporadic fibrothecomas, the TRIM37del2:TRIM37 ratio was increased. In normal ovary, TRIM37 was localized in the cytoplasm of stromal cells, especially theca cells surrounding developing follicles. TRIM37 transcript was found in all sporadic fibrothecomas examined, but 80% (20/25) of the tumors showed reduced or absent expression of TRIM37 protein. Allelic loss at the TRIM37 locus (17q22-23) was observed in 6% of sporadic fibrothecomas. Nearly half of the sporadic fibrothecomas showed evidence of CpG promoter methylation, suggesting promoter downregulation as one mechanism of reduced TRIM37 expression. In conclusion, inherited biallelic inactivation of TRIM37 (Mulibrey nanism) predisposes to both mesenchymal and epithelial ovarian tumors and dysregulation of TRIM37 may also be involved in the pathogenesis of sporadic fibrothecomas.
Topics: CpG Islands; DNA Methylation; DNA Mutational Analysis; Female; Humans; Immunohistochemistry; Loss of Heterozygosity; Mulibrey Nanism; Mutation; Nuclear Proteins; Ovarian Neoplasms; Promoter Regions, Genetic; Protein Isoforms; Thecoma; Tissue Array Analysis; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 19329943
DOI: 10.1038/modpathol.2009.13 -
Journal of Medical Genetics Feb 2004Mulibrey nanism (MUL) is an autosomal recessive disease caused by mutations in the TRIM37 gene encoding the peroxisomal TRIM37 protein of unknown function. In this work,...
Mulibrey nanism (MUL) is an autosomal recessive disease caused by mutations in the TRIM37 gene encoding the peroxisomal TRIM37 protein of unknown function. In this work, we analysed the clinical characteristics of 85 Finnish patients with MUL, most of whom were homozygous for the Finn major mutation of TRIM37. The patients' hospital records from birth to the time of the diagnosis at age 0.02-52 years (median 2.1 years) were retrospectively analysed. All except four of the patients (95%) had a prenatal onset growth failure without postnatal catch up growth. The mean length standard deviation score (SDS) was -3.1 and -4.0 at birth and at diagnosis, respectively. In infancy, feeding difficulties, and respiratory tract infections were the most common problems. Congestive heart failure and pericardial constriction were diagnosed during infancy in 12% and 6% of the patients, respectively. At the time of the diagnosis, characteristic craniofacial features of scaphocephaly, facial triangularity, high and broad forehead, and low nasal bridge were evident in over 90% of the patients. In addition, practically all patients were gracile and had thin extremities. Other findings included a peculiar high-pitched voice (96%), yellowish dots in ocular fundi (79%), cutaneous naevi flammei (65%), hepatomegaly (45%), and fibrous dysplasia of long bones (25%). Mild muscular hypotonicity (68%) was the only neurological abnormality. The clinical features of the Finnish patients with MUL formed a distinct entity. The most consistent findings were growth failure and characteristic craniofacial features. However, organ manifestations varied considerably in early childhood. Based on these findings, we propose new diagnostic criteria for MUL.
Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Craniofacial Abnormalities; Delivery, Obstetric; Dwarfism; Female; Humans; Infant; Infant, Newborn; Leg Bones; Male; Middle Aged; Mutation; Nuclear Proteins; Pregnancy; Proteins; Radiography; Retrospective Studies; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 14757854
DOI: 10.1136/jmg.2003.014118 -
The Journal of Tehran Heart Center Oct 2016Mulibrey nanism is a rare autosomal recessive syndrome caused by a mutation in the TRIM37 gene with severe growth retardation and multiple organ involvement. Early...
Mulibrey nanism is a rare autosomal recessive syndrome caused by a mutation in the TRIM37 gene with severe growth retardation and multiple organ involvement. Early diagnosis is important because 50% of the patients develop congestive heart failure owing to constrictive pericarditis, and this condition plays a critical role in the final prognosis. A 37-year-old female patient presented with symptoms of dyspnea on exertion and shortness of breath. She had severe growth failure and craniofacial dysmorphic feature. Cardiac evaluation showed constrictive pericarditis, moderate pulmonary hypertension, and mild pericardial effusion. The patient underwent pericardiectomy, but her thick and adhesive pericardium forced the surgeon to do partial pericardiotomy. Our report underlines the importance of attention to probable Mulibrey nanism when confronting patients with primary amenorrhea, growth retardation, and dysmorphic features. Early cardiac examination is of great significance in the course of the disorder, and patients must be pericardiectomized to relieve the symptoms and increase survival.
PubMed: 28496510
DOI: No ID Found