title: Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism.
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.
authors.affiliation: 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.
authors.forename: Kaisa M
authors.initials: KM
authors.lastname: Kettunen
authors.affiliation: Department of Pathology, Central Hospital of Tavastia, FI-13530 Hämeenlinna, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Karikoski
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio FI-70211, Finland.
authors.forename: Riikka H
authors.initials: RH
authors.lastname: Hämäläinen
authors.affiliation: Folkhälsan Institute of Genetics, FI-00290 Helsinki, Finland.
authors.forename: Teija T
authors.initials: TT
authors.lastname: Toivonen
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90220 Oulu, Finland.
authors.forename: Vasily D
authors.initials: VD
authors.lastname: Antonenkov
authors.affiliation: Neuroscience Center, University of Helsinki, FI-00790 Helsinki, Finland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kulesskaya
authors.affiliation: Neuroscience Center, University of Helsinki, FI-00790 Helsinki, Finland.
authors.forename: Vootele
authors.initials: V
authors.lastname: Voikar
authors.affiliation: Department of Anatomy, Faculty of Medicine, University of Helsinki, FI-00290 Helsinki, Finland Minerva Foundation Institute for Medical Research, FI-00290 Helsinki, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Hölttä-Vuori
authors.affiliation: Department of Anatomy, Faculty of Medicine, University of Helsinki, FI-00290 Helsinki, Finland Minerva Foundation Institute for Medical Research, FI-00290 Helsinki, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Ikonen
authors.affiliation: Biochemistry and Developmental Biology, Institute of Biomedicine, University of Helsinki, FI-00290 Helsinki, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Sainio
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Biomedicum, FI-00290 Helsinki, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Jalanko
authors.affiliation: Department of Endocrinology, Children's Hospital, University of Helsinki and Helsinki University Hospital, FI-00290 Helsinki, Finland.
authors.forename: Susann
authors.initials: S
authors.lastname: Karlberg
authors.affiliation: Department of Endocrinology, Children's Hospital, University of Helsinki and Helsinki University Hospital, FI-00290 Helsinki, Finland.
authors.forename: Niklas
authors.initials: N
authors.lastname: Karlberg
authors.affiliation: Department of Endocrinology, Children's Hospital, University of Helsinki and Helsinki University Hospital, FI-00290 Helsinki, Finland.
authors.forename: Marita
authors.initials: M
authors.lastname: Lipsanen-Nyman
authors.affiliation: Departments of Physiology and Pediatrics, University of Turku, FI-20520 Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Biomedicum, FI-00290 Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90220 Oulu, Finland.
authors.forename: J Kalervo
authors.initials: JK
authors.lastname: Hiltunen
authors.affiliation: Department of Nephrology and Transplantation, Children's Hospital, University of Helsinki and Helsinki University Hospital, FI-00290 Helsinki, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Jalanko
authors.affiliation: 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.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
keywords: Cardiomyopathy; Fatty liver; Growth failure; Infertility; Mulibrey nanism; Tumorigenesis