1. Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism
- Author
-
Anu Jalanko, Susann Karlberg, Niklas Karlberg, Matti Jauhiainen, J. Kalervo Hiltunen, Kirsi Sainio, Anna-Elina Lehesjoki, Riikka H. Hämäläinen, Teija T. Toivonen, Natalia Kulesskaya, Marita Lipsanen-Nyman, Vootele Voikar, Kaisa Kettunen, Jorma Toppari, Elina Ikonen, Hannu Jalanko, Maarit Hölttä-Vuori, Riitta Karikoski, Vasily D. Antonenkov, Institute for Molecular Medicine Finland, Neuroscience Center, Research Programme for Molecular Neurology, Research Programs Unit, Heikki Rauvala Research Group, Medicum, Department of Anatomy, Lipid Trafficking Lab, Department of Biochemistry and Developmental Biology, Clinicum, Children's Hospital, Endokrinologian yksikkö, Lastentautien yksikkö, Anna-Elina Lehesjoki / Principal Investigator, and HUS Children and Adolescents
- Subjects
0301 basic medicine ,Mulibrey nanism ,medicine.medical_specialty ,COILED-COIL PROTEIN ,QH301-705.5 ,Cardiomyopathy ,Science ,LUTEINIZING-HORMONE ,BIOGENESIS ,Congenic ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,FINGER PROTEIN TRIM37 ,0302 clinical medicine ,MOUSE MODELS ,Internal medicine ,Fatty liver ,medicine ,Biology (General) ,WILMS-TUMOR ,Testosterone ,ENZYME DEFICIENCIES ,Growth failure ,LIPID HOMEOSTASIS ,ta1184 ,3112 Neurosciences ,medicine.disease ,3. Good health ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Infertility ,3121 General medicine, internal medicine and other clinical medicine ,Tumorigenesis ,RAT ,3111 Biomedicine ,General Agricultural and Biological Sciences ,Carcinogenesis ,Luteinizing hormone ,PEROXISOMES ,030217 neurology & neurosurgery ,Germ cell ,Hormone ,Research Article - 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., Summary: A congenic Trim37-deficient mouse model recapitulates several features of the human disorder Mulibrey nanism, and thus provides a good model to study disease pathogenesis related to TRIM37 deficiency.
- Published
- 2016