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

Kaisa M Kettunen; Riitta Karikoski; Riikka H Hämäläinen; Teija T Toivonen; Vasily D Antonenkov; Natalia Kulesskaya; Vootele Voikar; Maarit Hölttä-Vuori; Elina Ikonen; Kirsi Sainio; Anu Jalanko; Susann Karlberg; Niklas Karlberg; Marita Lipsanen-Nyman; Jorma Toppari; Matti Jauhiainen; J Kalervo Hiltunen; Hannu Jalanko; Anna-Elina Lehesjoki

doi:10.1242/bio.016246

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

Biol Open. 2016 May 15;5(5):584-95. doi: 10.1242/bio.016246.

Authors

Kaisa M Kettunen¹, Riitta Karikoski², Riikka H Hämäläinen³, Teija T Toivonen⁴, Vasily D Antonenkov⁵, Natalia Kulesskaya⁶, Vootele Voikar⁶, Maarit Hölttä-Vuori⁷, Elina Ikonen⁷, Kirsi Sainio⁸, Anu Jalanko⁹, Susann Karlberg¹⁰, Niklas Karlberg¹⁰, Marita Lipsanen-Nyman¹⁰, Jorma Toppari¹¹, Matti Jauhiainen⁹, J Kalervo Hiltunen⁵, Hannu Jalanko¹², Anna-Elina Lehesjoki¹³

Affiliations

¹ Folkhälsan Institute of Genetics, FI-00290 Helsinki, Finland Research Programs Unit, Molecular Neurology, University of Helsinki, FI-00290 Helsinki, Finland Neuroscience Center, University of Helsinki, FI-00790 Helsinki, Finland Institute for Molecular Medicine Finland FIMM, University of Helsinki, FI-00290 Helsinki, Finland.
² Department of Pathology, Central Hospital of Tavastia, FI-13530 Hämeenlinna, Finland.
³ Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio FI-70211, Finland.
⁴ Folkhälsan Institute of Genetics, FI-00290 Helsinki, Finland.
⁵ Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90220 Oulu, Finland.
⁶ Neuroscience Center, University of Helsinki, FI-00790 Helsinki, Finland.
⁷ Department of Anatomy, Faculty of Medicine, University of Helsinki, FI-00290 Helsinki, Finland Minerva Foundation Institute for Medical Research, FI-00290 Helsinki, Finland.
⁸ Biochemistry and Developmental Biology, Institute of Biomedicine, University of Helsinki, FI-00290 Helsinki, Finland.
⁹ Genomics and Biomarkers Unit, National Institute for Health and Welfare, Biomedicum, FI-00290 Helsinki, Finland.
¹⁰ Department of Endocrinology, Children's Hospital, University of Helsinki and Helsinki University Hospital, FI-00290 Helsinki, Finland.
¹¹ Departments of Physiology and Pediatrics, University of Turku, FI-20520 Turku, Finland.
¹² Department of Nephrology and Transplantation, Children's Hospital, University of Helsinki and Helsinki University Hospital, FI-00290 Helsinki, Finland.
¹³ Folkhälsan Institute of Genetics, FI-00290 Helsinki, Finland Research Programs Unit, Molecular Neurology, University of Helsinki, FI-00290 Helsinki, Finland Neuroscience Center, University of Helsinki, FI-00790 Helsinki, Finland anna-elina.lehesjoki@helsinki.fi.

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.

Keywords: Cardiomyopathy; Fatty liver; Growth failure; Infertility; Mulibrey nanism; Tumorigenesis.