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.

TRIM37, a novel E3 ligase for PEX5-mediated peroxisomal matrix protein import

“…Interestingly, peroxisomes appear to be normal in TRIM37 knockout mice ( Kettunen et al, 2016 ). To resolve this apparent discrepancy, we silenced TRIM37 in a mouse cell line, Raw264.7.…”

CD4+ T Cell Defects in a Mulibrey Patient With Specific TRIM37 Mutations

“…Although it has been shown that the TRIM family was involved in innate immune response ( 14 ), none of the published evidence associated T lymphocyte derangement with TRIM37 mutations in MUL syndrome ( 5 , 10 ). It is likely that the specific TRIM37 mutations present in our MUL case ( 4 ) encoded for a defective TRIM37 protein, altering its conformation, cellular localization, and protein-protein interaction.…”

“…Accordingly, Haraldsson et al revealed humoral immunodeficiency in a patient affected by MUL syndrome (9). However, none of the published evidence reported adaptive immune response defects in MUL individuals (5,10).…”

Histone H2A Monoubiquitination in Neurodevelopmental Disorders

“…Likewise, further studies are needed to confirm the dynamics of H2A ubiquitination in primary cells from individuals with MUL. The spectrum of phenotypes described for the Trim37 −/− mouse model recapitulates many clinical features of MUL and thus provides a good model to study pathogenesis related to TRIM37 deficiency [52]. Despite the prominent neurological features of MUL, the role of TRIM37 in neural development has not been investigated.…”