Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism

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Kettunen , K M , Karikoski , R , Hamalainen , R H , Toivonen , T T , Antonenkov , V D , Kulesskaya , N , Voikar , V , Holtta-Vuori , M , Ikonen , E , Sainio , K , Jalanko , A , Karlberg , S , Karlberg , N , Lipsanen-Nyman , M , Toppari , J , Jauhiainen , M , Hiltunen , J K , Jalanko , H & Lehesjoki , A-E 2016 , ' Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism ' , Biology open , vol. 5 , no. 5 , pp. 584-595 .

Title: Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism
Author: Kettunen, Kaisa M.; Karikoski, Riitta; Hamalainen, Riikka H.; Toivonen, Teija T.; Antonenkov, Vasily D.; Kulesskaya, Natalia; Voikar, Vootele; Holtta-Vuori, Maarit; Ikonen, Elina; Sainio, Kirsi; Jalanko, Anu; Karlberg, Susann; Karlberg, Niklas; Lipsanen-Nyman, Marita; Toppari, Jorma; Jauhiainen, Matti; Hiltunen, J. Kalervo; Jalanko, Hannu; Lehesjoki, Anna-Elina
Contributor organization: Institute for Molecular Medicine Finland
Neuroscience Center
Research Programme for Molecular Neurology
Research Programs Unit
Heikki Rauvala Research Group
Department of Anatomy
Lipid Trafficking Lab
Department of Biochemistry and Developmental Biology
Children's Hospital
Endokrinologian yksikkö
Lastentautien yksikkö
Anna-Elina Lehesjoki / Principal Investigator
HUS Children and Adolescents
Date: 2016-05-15
Language: eng
Number of pages: 12
Belongs to series: Biology open
ISSN: 2046-6390
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 wildtype. 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.
Subject: Mulibrey nanism
Fatty liver
Growth failure
3111 Biomedicine
3112 Neurosciences
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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