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Anna-elina Lehesjoki - One of the best experts on this subject based on the ideXlab platform.
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Gynecological tumors in Mulibrey Nanism and role for RING finger protein TRIM37 in the pathogenesis of ovarian fibrothecomas
Modern Pathology, 2009Co-Authors: Susann Karlberg, Jukka Kallijärvi, Anna-elina Lehesjoki, Marita Lipsanen-nyman, Heini Lassus, Ralf ButzowAbstract: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. TRIM37 del2 was also found in normal ovary but in a proportion of sporadic fibrothecomas, the TRIM37 del2: 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.
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wilms tumor and novel trim37 mutations in an australian patient with Mulibrey Nanism
Clinical Genetics, 2006Co-Authors: Riikka H Hamalainen, Jukka Kallijärvi, David Mowat, Michael T Gabbett, Tracey A Obrien, Anna-elina LehesjokiAbstract:Mulibrey Nanism is a rare autosomal recessive growth disorder with prenatal onset, including occasional progressive cardiopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms' tumor. Mulibrey Nanism is prevalent in the Finnish population and appears extremely rare elsewhere. However, cases outside of Finland may be underdiagnosed or misdiagnosed as having the 3-M or Silver-Russell syndrome, two important differential diagnostic disorders. Here, we report the first Australian patient with Mulibrey Nanism, in whom the occurrence of Wilms' tumor suggested the correct diagnosis. This was confirmed by the identification of two novel mutations in tripartite motif protein 37 (TRIM37) encoding a RING finger ubiquitin E3 ligase. Both mutations, the p.Cys109Ser B-box missense mutation and the p.Glu271_Ser287del in-frame deletion in the tumor necrosis factor receptor associated factor (TRAF) domain alter the subcellular localization of TRIM37. As both the B-box and the TRAF domains are predicted to be important for mediating the protein-protein interactions, these mutations may help the understanding of the cellular interactions of TRIM37. Our findings imply the importance of early molecular diagnostics in cases of suspected Mulibrey Nanism and of identifying novel mutations with potential relevance for unraveling the underlying molecular pathology. Ultrasound surveillance for Wilms' tumor is recommended for children with Mulibrey Nanism.
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Tissue expression of the Mulibrey Nanism-associated Trim37 protein in embryonic and adult mouse tissues
Histochemistry and Cell Biology, 2006Co-Authors: Jukka Kallijärvi, Riikka H Hamalainen, Niklas Karlberg, Kirsi Sainio, Anna-elina LehesjokiAbstract:Mutations in the TRIM37 gene underlie Mulibrey Nanism (muscle–liver–brain–eye Nanism), a rare monogenic developmental disorder characterized by severe growth failure, characteristic dysmorphic features, cardiopathy, failure of sexual maturation, and metabolic syndrome. The TRIM37 protein, a member of the tripartite motif subfamily of RING finger proteins, is highly conserved between human and mouse. High evolutionary conservation is seen also at the gene level. We here show that the mouse Trim37 gene presents several alternative splice variants, including a testis-specific transcript with an additional 3′ exon. By Northern blot analysis the highest level of Trim37 mRNA was detected in testis and brain. In embryonic tissues, the Trim37 protein was detected in epithelia, including ducts of the developing pancreas, epithelium of the midgut and nasal epithelium. In adult mouse tissues, Trim37 immunoreactivity was detected in the central and peripheral nervous systems, including enteric ganglia, retina, and the adrenal medulla. Moreover, specific cellular populations in the adenohypophysis, pancreatic islets, intestine and gonads showed intense Trim37 staining. Both nuclear and granular cytoplasmic staining patterns were observed. These findings are in agreement with the clinical manifestations of Mulibrey Nanism and provide a basis for the future analysis of Trim37 knock-out mice.
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characterisation of the Mulibrey Nanism associated trim37 gene transcription initiation promoter region and alternative splicing
Gene, 2006Co-Authors: Riikka H Hamalainen, Jukka Kallijärvi, Tarja Joensuu, Anna-elina LehesjokiAbstract:Abstract The TRIM37 gene encodes a peroxisomal protein of unknown function. Mutations in TRIM37 underlie Mulibrey Nanism, a rare autosomal recessively inherited disorder with severe growth failure of prenatal onset, constrictive pericardium, hepatomegaly and characteristic dysmorphic features. Eleven Mulibrey Nanism-associated mutations have been identified. We here characterised TRIM37 further by mapping the transcription initiation site and promoter region as well as by analysing splice variants. By primer extension analysis, several transcription initiation sites were localised to a region between − 246 and − 373 relative to the ATG codon for translation initiation. Basal promoter activity was mapped within 600 nucleotides upstream from the translation initiation site using promoter-luciferase reporter constructs. Several alternative splice variants of TRIM37 exist in databases. Most of these predict non-functional protein products, are expressed at low levels and are thus likely to be targets for nonsense-mediated mRNA decay. A novel splice variant, TRIM37b , with an alternative termination codon and 3′untranslated region (UTR) transcribed from an exon 16 kb downstream from exon 24, predicts an identical protein product with the previously identified transcript, TRIM37a . As seen by Northern blot analysis and quantitative real-time PCR, both transcripts are highly expressed in testis, whereas in other tissues TRIM37a is prominent. The 3′UTR of the PPM1E gene in the opposite strand overlaps TRIM37b . These data suggest that TRIM37 expression is regulated by several mechanisms: through nonsense surveillance of non-functional transcripts, as well as through 3′UTR regulatory sequences and/or naturally occurring antisense RNAs especially in testis.
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trim37 defective in Mulibrey Nanism is a novel ring finger ubiquitin e3 ligase
Experimental Cell Research, 2005Co-Authors: Jukka Kallijärvi, Marita Lipsanennyman, Riikka H Hamalainen, Ulla Lahtinen, Jorma J Palvimo, Anna-elina LehesjokiAbstract:Mulibrey Nanism is an autosomal recessive prenatal-onset growth disorder characterized by dysmorphic features, cardiomyopathy, and hepatomegaly. Mutations in TRIM37 encoding a tripartite motif (TRIM, RING-B-box-coiled-coil)-family protein underlie Mulibrey Nanism. We investigated the ubiquitin ligase activity predicted for the RING domain of TRIM37 by analyzing its autoubiquitination. Full-length TRIM37 and its TRIM domain were highly polyubiquitinated when co-expressed with ubiquitin. Polyubiquitination was decreased in a mutant protein with disrupted RING domain (Cys35Ser;Cys36Ser) and in the Leu76Pro mutant protein, a disease-associated missense mutation affecting the TRIM domain of TRIM37. Bacterially produced GST-TRIM domain fusion protein, but not its Cys35Ser;Cys36Ser or Leu76Pro mutants, were polyubiquitinated in cell-free conditions, implying RING-dependent modification. Ubiquitin was also identified as an interaction partner for TRIM37 in a yeast two-hybrid screen. Ectopically expressed TRIM37 rapidly formed aggregates that were ubiquitin-, proteasome subunit-, and chaperone-positive in immunofluorescence analysis, defining them as aggresomes. The Cys35Ser;Cys36Ser mutant and the Leu76Pro and Gly322Val patient mutant proteins were markedly less prone to aggregation, implying that aggresomal targeting reflects a physiological function of TRIM37. These findings suggest that TRIM37 acts as a TRIM domain-dependent E3 ubiquitin ligase and imply defective ubiquitin-dependent degradation of an as-yet-unidentified target protein in the pathogenesis of Mulibrey Nanism.
Marita Lipsanennyman - One of the best experts on this subject based on the ideXlab platform.
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restriction of lung volumes but normal function of pulmonary tissue in Mulibrey Nanism
Pediatric Pulmonology, 2020Co-Authors: Johanna Sivunen, Marita Lipsanennyman, Susann Karlberg, Hannu Jalanko, M. Kupari, Paivi Piirila, Merja Kajosaari, Pekka Valmari, Anssi SovijarviAbstract:BACKGROUND Mulibrey Nanism (MUL) is a rare growth restriction disorder with multiple organ manifestations caused by genetic defects affecting the TRIM37 protein. A perimyocardial heart disease is the most serious manifestation. Many MUL children appear to suffer from airway obstruction related to infection or exercise, prompting use of inhaled therapies. Asthma medication is continued up to adolescence or even to adulthood due to persisting of symptoms. The pulmonary pathophysiology has previously not been evaluated in any MUL cohort. METHODS Thirty three finnish MUL patients (median age 20 years) were investigated with several lung function tests: spirometry with bronchodilatation test, single-breath diffusing capacity for carbon monoxide, single-breath lung volume measurements with helium dilution, and thoracic gas volume, airway resistance and specific conductance measurements with a body plethysmograph. As MUL typically affects body proportions, all variables were compared with reference values and with predicted values calculated from sitting height. RESULTS Total lung capacity and forced vital capacity were markedly reduced (total lung capacity [TLC] and forced vital capacity [FVC], P < .001, 51%-63% of predicted) and also forced expiratory volume in the first second was reduced (FEV1; P < .001, 47%-57%). No signs of airway obstruction was seen (normal FEV1/FVC and specific airway conductance SGaw). Diffusing capacity (DLCO) was decreased (P < .001, 60%-67%) but when related to alveolar volume it was increased (DLCO/VA, P < .001, 130%-148%). Bronchodilatation suggesting active asthma (FEV1 change ≥12% and ≥200 mL) was found only in one patient. CONCLUSION MUL patients typically have volume restriction of the lungs, but function of the pulmonary tissue remains intact. Evidence of asthma in lung function testing at adult age is rare.
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premature ovarian insufficiency and early depletion of the ovarian reserve in the monogenic Mulibrey Nanism disorder
Human Reproduction, 2018Co-Authors: Susann Karlberg, Aila Tiitinen, Henrik Alfthan, Marita LipsanennymanAbstract:STUDY QUESTION What is the timing of onset and clinical course of premature ovarian insufficiency (POI) in patients with Mulibrey Nanism (MUL), a monogenic disorder caused by mutations of the peroxisomal TRIM37 gene? SUMMARY ANSWER The number of ovarian follicles is highly reduced already in infant and young MUL girls and the majority of them will have early depletion of follicles resulting in clinical and biochemical signs of POI. WHAT IS KNOWN ALREADY Both female and male patients with MUL show failure of sexual maturation, signs of hypogonadism and infertility. STUDY DESIGN, SIZE, DURATION We studied the gonadal function, pubertal development and ovarian reserve in 33 MUL patients aged 5.1-47.3 years (median age 22.3) at the end of observation. The patients were followed between 2004 and 2014 and 19 pubertal or postpubertal patients were enrolled in a cross-sectional study. PARTICIPANTS/MATERIALS, SETTING, METHODS The period of postnatal activation of the hypothalamic-pituitary-gonadal axis (minipuberty), pubertal development and menstrual history were assessed longitudinally. The cross-sectional study included gynecological examination, analysis of reproductive hormones and ultrasonography with evaluation of ovarian volume and antral follicle count. MAIN RESULTS AND THE ROLE OF CHANCE Infant girls experienced a transient minipuberty with a high FSH surge. In childhood, gonadotropins were normal or slightly elevated but began to rise to hypergonadotropic levels in prepuberty. Anti-Mullerian hormone (AMH) levels remained undetectable or low throughout childhood. The onset of puberty occurred spontaneously and the median age at menarche was 12.5 years. Of the patients, 54% never attained regular menses and 10 years from menarche, only 8% of the women menstruated regularly. In the cross-sectional study, none of the patients had normal ovarian morphology under ultrasonography. Ovaries were hypoplastic and 82% had no or fewer than two visible antral follicles. AMH levels were undetectable in the vast majority (89%). LIMITATIONS, REASONS FOR CAUTION The Finnish MUL patients genotypically form a homogenous group and therefore it is possible, that different TRIM37 mutations lead to different hypogonadal phenotypes. However, to date there is no known genotype-phenotype correlation in MUL. WIDER IMPLICATIONS OF THE FINDINGS In MUL, AMH is a useful marker of ovarian function. MUL should be added to the list of syndromes associated with POI and correspondingly, TRIM37 should be added to the list of genes associated with POI. To our knowledge, TRIM37 is the first known gene coding for a peroxisomal membrane protein associated with female gonadal failure and infertility. Elucidating the role of syndromic genes in reproduction may aid in a greater understanding of ovarian biology. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Finnish Foundation for Pediatric Research, Finska Lakaresallskapet, the Sigrid Juselius Foundation and Helsinki University Hospital Research Funds. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER Not applicable.
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renal findings in patients with Mulibrey Nanism
Pediatric Nephrology, 2017Co-Authors: Johanna Sivunen, Marita Lipsanennyman, Susann Karlberg, Niklas Karlberg, Jouko Lohi, Hannu JalankoAbstract:Mulibrey Nanism (MUL) is a rare inherited disease caused by genetic defects affecting peroxisomal TRIM37 protein. MUL affects multiple organs, leading to growth retardation and early onset type 2 diabetes. We aimed to characterize the structure and function of kidneys and the urinary tract in a large cohort of Finnish MUL patients. Ultrasound, magnetic resonance imaging (MRI), and autopsy findings of the kidneys and urinary tract from 101 MUL patients were retrospectively analyzed. Renal function was examined using blood and urine biochemistry. Kidney pathology was assessed by histology and immunohistochemistry from biopsy and autopsy samples. Structural anomalies of the kidneys and urinary tract were found in 13 % of MUL patients and renal tumors and macroscopic cystic lesions in 14 % and 43 % respectively. Overall, kidney histology was well preserved, but glomerular cysts with a wide Bowman’s space were observed in most samples (87 %). Also, prominent and abundant blood vessels with thick walls were typically seen. Expression of endothelial cell markers and angiogenic growth factors PDGF-B and FGF1 (but not VEGF-A) was significantly increased in MUL kidneys. Markers of fibrosis and epithelial–mesenchymal transformation, α-SMA, and vimentin were moderately up-regulated. Despite radiological and histological changes, most MUL patients (age 0.2–51 years) had normal kidney function. However, 9 out of 36 patients (25 %) had hypertension and 6 out of 26 (23 %) had mildly decreased glomerular filtration. Genetic defects in the TRIM37 gene lead to an increased risk for kidney anomalies, renal tumors, and solitary cysts in addition to glomerular cystic lesions, but not to progressive deterioration of renal function.
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testicular failure and male infertility in the monogenic Mulibrey Nanism disorder
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Susann Karlberg, Niklas Karlberg, Hannu Jalanko, Jorma Toppari, Mirja Nurmio, Riitta Karikoski, Marita LipsanennymanAbstract:Context: Few monogenic mutations causing human male infertility have been identified to date. Objective: We studied pubertal development and fecundity in males with Mulibrey Nanism (MUL) caused by mutations in the TRIM37 gene. Design, Setting, and Patients: Twenty-eight male MUL patients of the Finnish national cohort aged 8.7 to 50.0 yr (median age, 28.8) at the end of observation were followed for 10 yr beginning from 2000–2001. Main Outcome Measures: Clinical characteristics, reproductive hormone levels, semen quality, and testicular histology were assessed. Results: The external genital phenotype was normal. In childhood and prepuberty, serum levels of FSH, LH, testosterone (T), and inhibin B were normal. Puberty started spontaneously at a median age of 12.6 yr (range, 11.1–15.0), and FSH, LH, T, and inhibin B levels increased adequately until midpuberty. Thereafter, testicular growth and virilization proceeded slowly. Concomitantly, FSH, and to a lesser extent LH, showed a progressive increase to hyp...
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high frequency of tumours in Mulibrey Nanism
The Journal of Pathology, 2009Co-Authors: Niklas Karlberg, Marita Lipsanennyman, Susann Karlberg, Riitta Karikoski, Sakari Mikkola, Hannu JalankoAbstract:Mulibrey Nanism (MUL) is a monogenic disorder with prenatal-onset growth failure, typical clinical characteristics, cardiopathy and tendency for a metabolic syndrome. It is caused by recessive mutations in the TRIM37 gene encoding for the peroxisomal TRIM37 protein with ubiquitin-ligase activity. In this work, the frequency and pathology of malignant and benign tumours were analysed in a national cohort of 89 Finnish MUL patients aged 0.7-76 years. The subjects had a clinical and radiological evaluation, and histological and immunohistocemical analyses on specimens obtained from biopsy, surgery or autopsy, were performed. The results show that the MUL patients have disturbed architecture with ectopic tissues and a high frequency of both benign and malignant tumours detectable in several internal organs. A total of 210 tumorous lesions were detected in 66/89 patients (74%). Fifteen malignancies occurred in 13 patients (15%), seven of them in the kidney (five Wilms' tumours), three in the thyroid gland, two gynaecological cancers, one gastrointestinal carcinoid tumour, one neuropituitary Langerhans cell histiocytosis and one case of acute lymphoblastic leukaemia (ALL). Tumours detected by radiology in the liver and other organs mainly comprised strongly dilated blood vessels (peliosis), vascularized cysts and nodular lesions. The lesions showed strong expression of the endothelial cell markers CD34 and CD31 as well as the myocyte marker alpha-smooth muscle actin (alpha-SMA). Our findings show that MUL is associated with frequent malignant tumours and benign adenomatous and vascular lesions, as well as disturbed organ development.
Jukka Kallijärvi - One of the best experts on this subject based on the ideXlab platform.
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Gynecological tumors in Mulibrey Nanism and role for RING finger protein TRIM37 in the pathogenesis of ovarian fibrothecomas
Modern Pathology, 2009Co-Authors: Susann Karlberg, Jukka Kallijärvi, Anna-elina Lehesjoki, Marita Lipsanen-nyman, Heini Lassus, Ralf ButzowAbstract: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. TRIM37 del2 was also found in normal ovary but in a proportion of sporadic fibrothecomas, the TRIM37 del2: 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.
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wilms tumor and novel trim37 mutations in an australian patient with Mulibrey Nanism
Clinical Genetics, 2006Co-Authors: Riikka H Hamalainen, Jukka Kallijärvi, David Mowat, Michael T Gabbett, Tracey A Obrien, Anna-elina LehesjokiAbstract:Mulibrey Nanism is a rare autosomal recessive growth disorder with prenatal onset, including occasional progressive cardiopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms' tumor. Mulibrey Nanism is prevalent in the Finnish population and appears extremely rare elsewhere. However, cases outside of Finland may be underdiagnosed or misdiagnosed as having the 3-M or Silver-Russell syndrome, two important differential diagnostic disorders. Here, we report the first Australian patient with Mulibrey Nanism, in whom the occurrence of Wilms' tumor suggested the correct diagnosis. This was confirmed by the identification of two novel mutations in tripartite motif protein 37 (TRIM37) encoding a RING finger ubiquitin E3 ligase. Both mutations, the p.Cys109Ser B-box missense mutation and the p.Glu271_Ser287del in-frame deletion in the tumor necrosis factor receptor associated factor (TRAF) domain alter the subcellular localization of TRIM37. As both the B-box and the TRAF domains are predicted to be important for mediating the protein-protein interactions, these mutations may help the understanding of the cellular interactions of TRIM37. Our findings imply the importance of early molecular diagnostics in cases of suspected Mulibrey Nanism and of identifying novel mutations with potential relevance for unraveling the underlying molecular pathology. Ultrasound surveillance for Wilms' tumor is recommended for children with Mulibrey Nanism.
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Tissue expression of the Mulibrey Nanism-associated Trim37 protein in embryonic and adult mouse tissues
Histochemistry and Cell Biology, 2006Co-Authors: Jukka Kallijärvi, Riikka H Hamalainen, Niklas Karlberg, Kirsi Sainio, Anna-elina LehesjokiAbstract:Mutations in the TRIM37 gene underlie Mulibrey Nanism (muscle–liver–brain–eye Nanism), a rare monogenic developmental disorder characterized by severe growth failure, characteristic dysmorphic features, cardiopathy, failure of sexual maturation, and metabolic syndrome. The TRIM37 protein, a member of the tripartite motif subfamily of RING finger proteins, is highly conserved between human and mouse. High evolutionary conservation is seen also at the gene level. We here show that the mouse Trim37 gene presents several alternative splice variants, including a testis-specific transcript with an additional 3′ exon. By Northern blot analysis the highest level of Trim37 mRNA was detected in testis and brain. In embryonic tissues, the Trim37 protein was detected in epithelia, including ducts of the developing pancreas, epithelium of the midgut and nasal epithelium. In adult mouse tissues, Trim37 immunoreactivity was detected in the central and peripheral nervous systems, including enteric ganglia, retina, and the adrenal medulla. Moreover, specific cellular populations in the adenohypophysis, pancreatic islets, intestine and gonads showed intense Trim37 staining. Both nuclear and granular cytoplasmic staining patterns were observed. These findings are in agreement with the clinical manifestations of Mulibrey Nanism and provide a basis for the future analysis of Trim37 knock-out mice.
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characterisation of the Mulibrey Nanism associated trim37 gene transcription initiation promoter region and alternative splicing
Gene, 2006Co-Authors: Riikka H Hamalainen, Jukka Kallijärvi, Tarja Joensuu, Anna-elina LehesjokiAbstract:Abstract The TRIM37 gene encodes a peroxisomal protein of unknown function. Mutations in TRIM37 underlie Mulibrey Nanism, a rare autosomal recessively inherited disorder with severe growth failure of prenatal onset, constrictive pericardium, hepatomegaly and characteristic dysmorphic features. Eleven Mulibrey Nanism-associated mutations have been identified. We here characterised TRIM37 further by mapping the transcription initiation site and promoter region as well as by analysing splice variants. By primer extension analysis, several transcription initiation sites were localised to a region between − 246 and − 373 relative to the ATG codon for translation initiation. Basal promoter activity was mapped within 600 nucleotides upstream from the translation initiation site using promoter-luciferase reporter constructs. Several alternative splice variants of TRIM37 exist in databases. Most of these predict non-functional protein products, are expressed at low levels and are thus likely to be targets for nonsense-mediated mRNA decay. A novel splice variant, TRIM37b , with an alternative termination codon and 3′untranslated region (UTR) transcribed from an exon 16 kb downstream from exon 24, predicts an identical protein product with the previously identified transcript, TRIM37a . As seen by Northern blot analysis and quantitative real-time PCR, both transcripts are highly expressed in testis, whereas in other tissues TRIM37a is prominent. The 3′UTR of the PPM1E gene in the opposite strand overlaps TRIM37b . These data suggest that TRIM37 expression is regulated by several mechanisms: through nonsense surveillance of non-functional transcripts, as well as through 3′UTR regulatory sequences and/or naturally occurring antisense RNAs especially in testis.
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trim37 defective in Mulibrey Nanism is a novel ring finger ubiquitin e3 ligase
Experimental Cell Research, 2005Co-Authors: Jukka Kallijärvi, Marita Lipsanennyman, Riikka H Hamalainen, Ulla Lahtinen, Jorma J Palvimo, Anna-elina LehesjokiAbstract:Mulibrey Nanism is an autosomal recessive prenatal-onset growth disorder characterized by dysmorphic features, cardiomyopathy, and hepatomegaly. Mutations in TRIM37 encoding a tripartite motif (TRIM, RING-B-box-coiled-coil)-family protein underlie Mulibrey Nanism. We investigated the ubiquitin ligase activity predicted for the RING domain of TRIM37 by analyzing its autoubiquitination. Full-length TRIM37 and its TRIM domain were highly polyubiquitinated when co-expressed with ubiquitin. Polyubiquitination was decreased in a mutant protein with disrupted RING domain (Cys35Ser;Cys36Ser) and in the Leu76Pro mutant protein, a disease-associated missense mutation affecting the TRIM domain of TRIM37. Bacterially produced GST-TRIM domain fusion protein, but not its Cys35Ser;Cys36Ser or Leu76Pro mutants, were polyubiquitinated in cell-free conditions, implying RING-dependent modification. Ubiquitin was also identified as an interaction partner for TRIM37 in a yeast two-hybrid screen. Ectopically expressed TRIM37 rapidly formed aggregates that were ubiquitin-, proteasome subunit-, and chaperone-positive in immunofluorescence analysis, defining them as aggresomes. The Cys35Ser;Cys36Ser mutant and the Leu76Pro and Gly322Val patient mutant proteins were markedly less prone to aggregation, implying that aggresomal targeting reflects a physiological function of TRIM37. These findings suggest that TRIM37 acts as a TRIM domain-dependent E3 ubiquitin ligase and imply defective ubiquitin-dependent degradation of an as-yet-unidentified target protein in the pathogenesis of Mulibrey Nanism.
Riikka H Hamalainen - One of the best experts on this subject based on the ideXlab platform.
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trim37 deficient mice recapitulate several features of the multi organ disorder Mulibrey Nanism
Biology Open, 2016Co-Authors: Kaisa Kettunen, Riikka H Hamalainen, Riitta Karikoski, Teija T Toivonen, Vasily D Antonenkov, Natalia Kulesskaya, Vootele Voikar, Maarit Holttavuori, Elina Ikonen, Kirsi SainioAbstract:ABSTRACT 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.
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Refractory congestive heart failure following delayed pericardectomy in a 12-year-old child with Mulibrey Nanism due to a novel mutation in TRIM37
European Journal of Pediatrics, 2013Co-Authors: Matthias Kumpf, Riikka H Hamalainen, Michael Hofbeck, Winfried BadenAbstract:Mulibrey Nanism (MUL) is a rare autosomal recessive disorder with severe primordial growth retardation and multiorgan involvement, caused by mutations in TRIM37. Early clinical detection is important since more than 50 % of the patients develop congestive heart failure. We report a 12-year-old patient who presented in infancy with severe growth retardation, dysmorphic features, and cleft palate. Clinical diagnosis of MUL was established at the age of 5 years. Postmortem, molecular diagnostic confirmed MUL as a novel 1-bp deletion (c.1233delA) in exon 14 of the TRIM37 coding region. Cardiac examination at the age of 6 years revealed constrictive pericarditis with significant elevation of atrial filling pressures, consecutive hepatomegaly, and protein loosing enteropathy. Since the parents refused pericardectomy, surgery was delayed until the age of 12 years, when congestive heart failure deteriorated. Despite pericardectomy, the boy died from persistent right heart failure. Conclusion : Our report underlines the necessity of early clinical diagnosis of Mulibrey Nanism. Careful cardiologic examination is required to detect constrictive pericarditis, which is a major factor of mortality in these patients. Pericardectomy should be performed early, to avoid sequelae of persisting congestive heart failure.
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a novel mutation in trim37 is associated with Mulibrey Nanism in a turkish boy
Clinical Dysmorphology, 2007Co-Authors: T Doganc, Riikka H Hamalainen, N Alpan, Onur Konuk, A E Lehesjoki, Mustafa TekinAbstract:Mulibrey Nanism is a rare autosomal-recessive disorder characterized by prenatal onset severe growth retardation and pericardial constriction associated with abnormalities of muscle, liver, brain and eye. More than 80% of previously reported patients are of Finnish origin in whom a founder mutation in the TRIM37 gene have been described. We report on a 7-year-old Turkish boy who presented with classical phenotypic features of Mulibrey Nanism. Mutation screening of the TRIM37 gene revealed that the proband had a homozygous two base pair deletion, c.1894_1895delGA, resulting in a frame-shift and a premature termination codon. Our proband is one of the rare examples of Mulibrey Nanism outside Finland and extends the mutation spectrum in this disorder.
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wilms tumor and novel trim37 mutations in an australian patient with Mulibrey Nanism
Clinical Genetics, 2006Co-Authors: Riikka H Hamalainen, Jukka Kallijärvi, David Mowat, Michael T Gabbett, Tracey A Obrien, Anna-elina LehesjokiAbstract:Mulibrey Nanism is a rare autosomal recessive growth disorder with prenatal onset, including occasional progressive cardiopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms' tumor. Mulibrey Nanism is prevalent in the Finnish population and appears extremely rare elsewhere. However, cases outside of Finland may be underdiagnosed or misdiagnosed as having the 3-M or Silver-Russell syndrome, two important differential diagnostic disorders. Here, we report the first Australian patient with Mulibrey Nanism, in whom the occurrence of Wilms' tumor suggested the correct diagnosis. This was confirmed by the identification of two novel mutations in tripartite motif protein 37 (TRIM37) encoding a RING finger ubiquitin E3 ligase. Both mutations, the p.Cys109Ser B-box missense mutation and the p.Glu271_Ser287del in-frame deletion in the tumor necrosis factor receptor associated factor (TRAF) domain alter the subcellular localization of TRIM37. As both the B-box and the TRAF domains are predicted to be important for mediating the protein-protein interactions, these mutations may help the understanding of the cellular interactions of TRIM37. Our findings imply the importance of early molecular diagnostics in cases of suspected Mulibrey Nanism and of identifying novel mutations with potential relevance for unraveling the underlying molecular pathology. Ultrasound surveillance for Wilms' tumor is recommended for children with Mulibrey Nanism.
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Tissue expression of the Mulibrey Nanism-associated Trim37 protein in embryonic and adult mouse tissues
Histochemistry and Cell Biology, 2006Co-Authors: Jukka Kallijärvi, Riikka H Hamalainen, Niklas Karlberg, Kirsi Sainio, Anna-elina LehesjokiAbstract:Mutations in the TRIM37 gene underlie Mulibrey Nanism (muscle–liver–brain–eye Nanism), a rare monogenic developmental disorder characterized by severe growth failure, characteristic dysmorphic features, cardiopathy, failure of sexual maturation, and metabolic syndrome. The TRIM37 protein, a member of the tripartite motif subfamily of RING finger proteins, is highly conserved between human and mouse. High evolutionary conservation is seen also at the gene level. We here show that the mouse Trim37 gene presents several alternative splice variants, including a testis-specific transcript with an additional 3′ exon. By Northern blot analysis the highest level of Trim37 mRNA was detected in testis and brain. In embryonic tissues, the Trim37 protein was detected in epithelia, including ducts of the developing pancreas, epithelium of the midgut and nasal epithelium. In adult mouse tissues, Trim37 immunoreactivity was detected in the central and peripheral nervous systems, including enteric ganglia, retina, and the adrenal medulla. Moreover, specific cellular populations in the adenohypophysis, pancreatic islets, intestine and gonads showed intense Trim37 staining. Both nuclear and granular cytoplasmic staining patterns were observed. These findings are in agreement with the clinical manifestations of Mulibrey Nanism and provide a basis for the future analysis of Trim37 knock-out mice.
Hannu Jalanko - One of the best experts on this subject based on the ideXlab platform.
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restriction of lung volumes but normal function of pulmonary tissue in Mulibrey Nanism
Pediatric Pulmonology, 2020Co-Authors: Johanna Sivunen, Marita Lipsanennyman, Susann Karlberg, Hannu Jalanko, M. Kupari, Paivi Piirila, Merja Kajosaari, Pekka Valmari, Anssi SovijarviAbstract:BACKGROUND Mulibrey Nanism (MUL) is a rare growth restriction disorder with multiple organ manifestations caused by genetic defects affecting the TRIM37 protein. A perimyocardial heart disease is the most serious manifestation. Many MUL children appear to suffer from airway obstruction related to infection or exercise, prompting use of inhaled therapies. Asthma medication is continued up to adolescence or even to adulthood due to persisting of symptoms. The pulmonary pathophysiology has previously not been evaluated in any MUL cohort. METHODS Thirty three finnish MUL patients (median age 20 years) were investigated with several lung function tests: spirometry with bronchodilatation test, single-breath diffusing capacity for carbon monoxide, single-breath lung volume measurements with helium dilution, and thoracic gas volume, airway resistance and specific conductance measurements with a body plethysmograph. As MUL typically affects body proportions, all variables were compared with reference values and with predicted values calculated from sitting height. RESULTS Total lung capacity and forced vital capacity were markedly reduced (total lung capacity [TLC] and forced vital capacity [FVC], P < .001, 51%-63% of predicted) and also forced expiratory volume in the first second was reduced (FEV1; P < .001, 47%-57%). No signs of airway obstruction was seen (normal FEV1/FVC and specific airway conductance SGaw). Diffusing capacity (DLCO) was decreased (P < .001, 60%-67%) but when related to alveolar volume it was increased (DLCO/VA, P < .001, 130%-148%). Bronchodilatation suggesting active asthma (FEV1 change ≥12% and ≥200 mL) was found only in one patient. CONCLUSION MUL patients typically have volume restriction of the lungs, but function of the pulmonary tissue remains intact. Evidence of asthma in lung function testing at adult age is rare.
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Renal findings in patients with Mulibrey Nanism
Pediatric Nephrology, 2017Co-Authors: Johanna Sivunen, Marita Lipsanen-nyman, Susann Karlberg, Niklas Karlberg, Jouko Lohi, Hannu JalankoAbstract:Background Mulibrey Nanism (MUL) is a rare inherited disease caused by genetic defects affecting peroxisomal TRIM37 protein. MUL affects multiple organs, leading to growth retardation and early onset type 2 diabetes. We aimed to characterize the structure and function of kidneys and the urinary tract in a large cohort of Finnish MUL patients. Methods Ultrasound, magnetic resonance imaging (MRI), and autopsy findings of the kidneys and urinary tract from 101 MUL patients were retrospectively analyzed. Renal function was examined using blood and urine biochemistry. Kidney pathology was assessed by histology and immunohistochemistry from biopsy and autopsy samples. Results Structural anomalies of the kidneys and urinary tract were found in 13 % of MUL patients and renal tumors and macroscopic cystic lesions in 14 % and 43 % respectively. Overall, kidney histology was well preserved, but glomerular cysts with a wide Bowman’s space were observed in most samples (87 %). Also, prominent and abundant blood vessels with thick walls were typically seen. Expression of endothelial cell markers and angiogenic growth factors PDGF-B and FGF1 (but not VEGF-A) was significantly increased in MUL kidneys. Markers of fibrosis and epithelial–mesenchymal transformation, α-SMA, and vimentin were moderately up-regulated. Despite radiological and histological changes, most MUL patients (age 0.2–51 years) had normal kidney function. However, 9 out of 36 patients (25 %) had hypertension and 6 out of 26 (23 %) had mildly decreased glomerular filtration. Conclusions Genetic defects in the TRIM37 gene lead to an increased risk for kidney anomalies, renal tumors, and solitary cysts in addition to glomerular cystic lesions, but not to progressive deterioration of renal function.
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renal findings in patients with Mulibrey Nanism
Pediatric Nephrology, 2017Co-Authors: Johanna Sivunen, Marita Lipsanennyman, Susann Karlberg, Niklas Karlberg, Jouko Lohi, Hannu JalankoAbstract:Mulibrey Nanism (MUL) is a rare inherited disease caused by genetic defects affecting peroxisomal TRIM37 protein. MUL affects multiple organs, leading to growth retardation and early onset type 2 diabetes. We aimed to characterize the structure and function of kidneys and the urinary tract in a large cohort of Finnish MUL patients. Ultrasound, magnetic resonance imaging (MRI), and autopsy findings of the kidneys and urinary tract from 101 MUL patients were retrospectively analyzed. Renal function was examined using blood and urine biochemistry. Kidney pathology was assessed by histology and immunohistochemistry from biopsy and autopsy samples. Structural anomalies of the kidneys and urinary tract were found in 13 % of MUL patients and renal tumors and macroscopic cystic lesions in 14 % and 43 % respectively. Overall, kidney histology was well preserved, but glomerular cysts with a wide Bowman’s space were observed in most samples (87 %). Also, prominent and abundant blood vessels with thick walls were typically seen. Expression of endothelial cell markers and angiogenic growth factors PDGF-B and FGF1 (but not VEGF-A) was significantly increased in MUL kidneys. Markers of fibrosis and epithelial–mesenchymal transformation, α-SMA, and vimentin were moderately up-regulated. Despite radiological and histological changes, most MUL patients (age 0.2–51 years) had normal kidney function. However, 9 out of 36 patients (25 %) had hypertension and 6 out of 26 (23 %) had mildly decreased glomerular filtration. Genetic defects in the TRIM37 gene lead to an increased risk for kidney anomalies, renal tumors, and solitary cysts in addition to glomerular cystic lesions, but not to progressive deterioration of renal function.
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testicular failure and male infertility in the monogenic Mulibrey Nanism disorder
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Susann Karlberg, Niklas Karlberg, Hannu Jalanko, Jorma Toppari, Mirja Nurmio, Riitta Karikoski, Marita LipsanennymanAbstract:Context: Few monogenic mutations causing human male infertility have been identified to date. Objective: We studied pubertal development and fecundity in males with Mulibrey Nanism (MUL) caused by mutations in the TRIM37 gene. Design, Setting, and Patients: Twenty-eight male MUL patients of the Finnish national cohort aged 8.7 to 50.0 yr (median age, 28.8) at the end of observation were followed for 10 yr beginning from 2000–2001. Main Outcome Measures: Clinical characteristics, reproductive hormone levels, semen quality, and testicular histology were assessed. Results: The external genital phenotype was normal. In childhood and prepuberty, serum levels of FSH, LH, testosterone (T), and inhibin B were normal. Puberty started spontaneously at a median age of 12.6 yr (range, 11.1–15.0), and FSH, LH, T, and inhibin B levels increased adequately until midpuberty. Thereafter, testicular growth and virilization proceeded slowly. Concomitantly, FSH, and to a lesser extent LH, showed a progressive increase to hyp...
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high frequency of tumours in Mulibrey Nanism
The Journal of Pathology, 2009Co-Authors: Niklas Karlberg, Marita Lipsanennyman, Susann Karlberg, Riitta Karikoski, Sakari Mikkola, Hannu JalankoAbstract:Mulibrey Nanism (MUL) is a monogenic disorder with prenatal-onset growth failure, typical clinical characteristics, cardiopathy and tendency for a metabolic syndrome. It is caused by recessive mutations in the TRIM37 gene encoding for the peroxisomal TRIM37 protein with ubiquitin-ligase activity. In this work, the frequency and pathology of malignant and benign tumours were analysed in a national cohort of 89 Finnish MUL patients aged 0.7-76 years. The subjects had a clinical and radiological evaluation, and histological and immunohistocemical analyses on specimens obtained from biopsy, surgery or autopsy, were performed. The results show that the MUL patients have disturbed architecture with ectopic tissues and a high frequency of both benign and malignant tumours detectable in several internal organs. A total of 210 tumorous lesions were detected in 66/89 patients (74%). Fifteen malignancies occurred in 13 patients (15%), seven of them in the kidney (five Wilms' tumours), three in the thyroid gland, two gynaecological cancers, one gastrointestinal carcinoid tumour, one neuropituitary Langerhans cell histiocytosis and one case of acute lymphoblastic leukaemia (ALL). Tumours detected by radiology in the liver and other organs mainly comprised strongly dilated blood vessels (peliosis), vascularized cysts and nodular lesions. The lesions showed strong expression of the endothelial cell markers CD34 and CD31 as well as the myocyte marker alpha-smooth muscle actin (alpha-SMA). Our findings show that MUL is associated with frequent malignant tumours and benign adenomatous and vascular lesions, as well as disturbed organ development.