Birgit Rathkolb

• Dr. med. vet.
• Guest scientist at Helmholtz Center Munich, German Mouse Clinic at Ludwig-Maximilians-Universität in Munich

Hutchinson–Gilford progeria syndrome (HGPS) is a rare, fatal, and premature aging disorder caused by progerin, a truncated form of lamin A that disrupts nuclear architecture, induces systemic inflammation, and accelerates senescence. While the farnesyltransferase inhibitor lonafarnib extends the lifespan by limiting progerin farnesylation, it does...

The pig is a valuable animal model in diabetes research; however, standardized protocols are essential for evaluating in vivo metabolism. Here, we present a protocol for in vivo assessment of glucose control and insulin secretion and sensitivity in the pig. We describe steps for catheter implantation, testing of intravenous glucose tolerance, perfo...

Telomere length regulation is essential for genome stability as short telomeres can trigger cellular senescence and apoptosis constituting an integral aspect of biological aging. Telomere biology disorders (TBDs) such as dyskeratosis congenita (DC) are rare, inherited diseases with known mutations in at least 16 different genes encoding components...

The lncRNA Crossfirre was identified as an imprinted X-linked gene, and is transcribed antisense to the trans-acting lncRNA Firre. The Firre locus forms an inactive-X-specific interaction with Dxz4, both loci providing the platform for the largest conserved chromatin structures. Here, we characterize the epigenetic profile of these loci, revealing...

Exposure to nanoparticles (NPs) is frequently associated with adverse cardiovascular effects. In contrast, NPs in nanomedicine hold great promise for precise lung‐specific drug delivery, especially considering the extensive pulmonary capillary network that facilitates interactions with bloodstream‐suspended particles. Therefore, exact knowledge abo...

Regeneration of insulin-producing β-cells is an alternative avenue to manage diabetes, and it is crucial to unravel this process in vivo during physiological responses to the lack of β-cells. Here, we aimed to characterize how hepatocytes can contribute to β-cell regeneration, either directly or indirectly via secreted proteins or metabolites, in a...

Purpose Growth hormone (GH) is a central regulator of β-cell proliferation, insulin secretion and sensitivity. Aim of this study was to investigate the effect of GH insensitivity on pancreatic β-cell histomorphology and consequences for metabolism in vivo. Methods Pancreata from pigs with growth hormone receptor deficiency (GHR-KO, n = 12) were an...

Thyroid hormone (TH) effects are mediated through TH receptors (TRs) TRα1, TRβ1, and TRβ2. The TRs bind to the DNA and regulate expression of TH target genes (canonical signaling). In addition, they mediate activation of signaling pathways (noncanonical signaling). Whether noncanonical TR action contributes to the spectrum of TH effects is largely...

Regeneration of insulin-producing beta-cells is an alternative avenue to manage diabetes, and it is crucial to unravel this process in vivo during physiological responses to the lack of beta-cells. Here, we aimed to characterize how hepatocytes can contribute to beta-cell regeneration in a zebrafish model of beta-cell ablation. Using lineage-tracin...

Exposure to nanoparticles (NPs) is frequently associated with adverse cardiovascular effects. In contrast, NPs in nanomedicine hold great promise for precise lung-specific drug delivery, especially considering the extensive pulmonary capillary network that facilitates interactions with bloodstream-suspended particles. Therefore, exact knowledge abo...

Obesity is a global health problem characterized by excessive fat accumulation, driven by adipogenesis and lipid accumulation. Long non‐coding RNAs (lncRNAs) have recently been implicated in regulating adipogenesis and adipose tissue function. Mouse lncRNA U90926 was previously identified as a repressor of in vitro adipogenesis in 3T3‐L1 preadipocy...

Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we a...

Thyroid hormone (TH) effects are mediated through TH receptors (TRs) TRα1, TRβ1, and TRβ2. The TRs bind to thyroid hormone responsive elements on the DNA and regulate expression of TH target genes as ligand dependent transcription factors (canonical signaling). In addition, the TRs α and β mediate activation of signaling pathways, e.g. the PI3K/AKT...

Objective: To gain mechanistic insights into adverse effects of maternal hyperglycemia on the liver of neonates, we performed a multi-omics analysis of liver tissue from piglets developed in genetically diabetic (mutant INS gene induced diabetes of youth; MIDY) or wild-type (WT) pigs. Methods: Proteome, metabolome and lipidome profiles of liver...

DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutat...

Rare diseases (RDs) are a challenge for medicine due to their heterogeneous clinical manifestations and low prevalence. There is a lack of specific treatments and only a few hundred of the approximately 7,000 RDs have an approved regime. Rapid technological development in genome sequencing enables the mass identification of potential candidates tha...

The alternative oxidase, AOX, provides a by-pass of the cytochrome segment of the mitochondrial respiratory chain when the chain is unavailable. AOX is absent from mammals, but AOX from Ciona intestinalis is benign when expressed in mice. Although non-protonmotive, so does not contribute directly to ATP production, it has been shown to modify and i...

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below 30 years of age. Many monogenic forms have been discovered mainly due to comprehensive genetic testing like exome sequencing (ES). However, disease-causing variants in known disease-associated genes still only explain...

DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutat...

Background: Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OT...

Thioredoxin-interacting protein (TXNIP) is a key player in the endocrine pancreas; it induces beta cell apoptosis, such that TXNIP deficiency promotes beta cell survival. To study its function in more detail, we generated transgenic mice with ubiquitous overexpression of TXNIP. CBATXNIP/+ mice were investigated under basal conditions and after bein...

Ubiquinol cytochrome c reductase hinge protein (UQCRH) is required for the electron transfer between cytochrome c 1 and c of the mitochondrial cytochrome bc 1 Complex (CIII). A two-exon deletion in the human UQCRH gene has recently been identified as the cause for a rare familial mitochondrial disorder. Deletion of the corresponding gene in the mou...

Background Dietary carbohydrates and fats are intrinsically correlated within the habitual diet. We aimed to disentangle the associations of starch and sucrose from those of fat, in relation to allergic sensitization, asthma and rhinoconjuctivitis prevalence in humans, and to investigate underlying mechanisms using murine models. Methods Epidemiol...

Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to ther...

Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific pathologies. Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/...

Cardiometabolic diseases, such as type 2 diabetes and cardiovascular disease, have a high public health burden. Understanding the genetically-determined regulation of proteins that are dysregulated in disease can help to dissect the complex biology underpinning them. Here, we perform a protein quantitative trait locus (pQTL) analysis of 255 serum p...

Animal models are an indispensable platform used in various research disciplines, enabling, for example, studies of basic biological mechanisms, pathological processes and new therapeutic interventions. In this study, we applied magnetic resonance imaging (MRI) to characterize the clinical picture of a novel N-ethyl-N-nitrosourea-induced Kit -mutan...

Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT-mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to ther...

Rare diseases (RDs) are a challenge for medicine due to their heterogeneous clinical manifestation and low prevalence. There is a lack of specific treatments and only a few hundred of the approximately 7.000 RDs have an approved regime. Rapid technological development in genome sequencing enables the mass identification of potential candidates that...

Mitochondrial DNA (mtDNA) maintenance disorders are caused by mutations in ubiquitously expressed nuclear genes and lead to syndromes with variable disease severity and tissue-specific phenotypes. Loss of function mutations in the gene encoding the mitochondrial genome and maintenance exonuclease 1 (MGME1) result in deletions and depletion of mtDNA...

Suitable animal models are essential for translational research, especially in the case of complex, multifactorial conditions, such as obesity. The non-inbred mouse (Mus musculus) line Titan, also known as DU6, is one of the world’s longest selection experiments for high body mass and was previously described as a model for metabolic healthy (benig...

Current concepts regarding the biology of aging are based on studies aimed at identifying factors regulating natural lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific sets of pathologies, rather than by general physiological decline. Here, we employed large-scale phenotypi...

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural...

Understanding the shared genetic aetiology of psychiatric and medical comorbidity in neurodevelopmental disorders (NDDs) could improve patient diagnosis, stratification and treatment options. Rare TANC2 (Tetratricopeptide Repeat, Ankyrin Repeat and Coiled-Coil Containing 2) disrupting variants were disease-causing in NDD patients. This post-synapti...

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to energetic homeostasis by disrupting energy producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut) type MMAuria. We found...

Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous delet...

Trpc7 (transient receptor potential cation channel, subfamily C, member 7; 862 amino acids) knockout mice are described showing no clear phenotypic alterations, therefore, the functional relevance of the gene remains unclear. A complementary approach for the functional analysis of a given gene is the examination of individuals harbouring a mutant a...

Pathogenic variants in the WDR45 (OMIM: 300,526) gene on chromosome Xp11 are the genetic cause of a rare neurological disorder characterized by increased iron deposition in the basal ganglia. As WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, the disease has been named Beta-Propeller Protein-Associated Neurodegene...

The NADPH oxidase Nox4 is a hydrogen peroxide (H2O2)-producing enzyme, with the highest expression in the kidney. As the kidney is involved in volume and blood pressure control through sodium handling, we set out to determine the impact of a low sodium diet on these parameters in WT and Nox4-/- mice. Nox4 expression in the murine kidney was restric...

Mice are important models for biomedical research by providing the possibility of standardizing genetic background and environmental conditions, which both affect phenotypic variability. Use of both sexes in experiments is strongly recommended because of possible differences in the outcome. However, sex-specific phenotypic variability is discussed...

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to energetic homeostasis by disrupting energy producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut) type MMAuria. We found...

The transcription factor PAX6 is involved in the development of the eye and pancreatic islets, besides being associated with sleep-wake cycles. Here, we investigated a point mutation in the RED subdomain of PAX6, previously described in a human patient, to present a comprehensive study of a homozygous Pax6 mutation in the context of adult mammalian...

Expansion of a (G4C2)n repeat in C9orf72 causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the link of the five repeat-encoded dipeptide repeat (DPR) proteins to neuroinflammation, TDP-43 pathology, and neurodegeneration is unclear. Poly-PR is most toxic in vitro, but poly-GA is far more abundant in patients. To dire...

Recently, covalent modifications of RNA, such as methylation, have emerged as key regulators of all aspects of RNA biology and have been implicated in numerous diseases, for instance, cancer. Here, we undertook a combination of in vitro and in vivo screens to test 78 potential methyltransferases for their roles in hepatocellular carcinoma (HCC) cel...

Metabolic syndrome is widespread and negatively impacts healthy longevity but takes years to study in mammalian models, delaying translational applications. To address this, we characterized the unique polygenic 'Titan' mouse (110 grams average) with a healthy lifespan of only 4 months that was generated by 45 years of breeding selection. Titan mic...

Objective The liver is a central target organ of growth hormone (GH), which stimulates the synthesis of insulin-like growth factor 1 (IGF1) and affects multiple biochemical pathways. A systematic multi-omics analysis of GH effects in the liver has not been performed. GH receptor (GHR) deficiency is a unique model for studying consequences of lackin...

The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In...

Regulation of cellular iron homeostasis is crucial as both iron excess and deficiency cause hematological and neurodegenerative diseases. Here we show that mice lacking iron-regulatory protein 2 (Irp2), a regulator of cellular iron homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake protein transferrin receptor 1 (T...

Isolated methylmalonic aciduria (MMAuria) is primarily caused by deficiency of methylmalonyl-CoA mutase (MMUT or MUT). Biochemically, MUT deficiency results in the accumulation of methylmalonic acid (MMA), propionyl-carnitine (C3) and other metabolites. Patients often exhibit lethargy, failure to thrive and metabolic decompensation leading to coma...

Tissue factor is highly expressed in sub-endothelial tissue. The extracellular allosteric disulfide bond Cys186-Cys209 of human tissue factor shows high evolutionary conservation and in vitro evidence suggests that it significantly contributes to tissue factor procoagulant activity. To investigate the role of this allosteric disulfide bond in vivo,...

Alongside the obesity epidemic, the prevalence of maternal diabetes is rising worldwide, and adverse effects on fetal development and metabolic disturbances in the offspring's later life have been described. To clarify whether metabolic programming effects are due to mild maternal hyperglycemia without confounding obesity, we investigated wild-type...

Glutathione peroxidase 4 (GPX4) is unique as it is the only enzyme that can prevent detrimental lipid peroxidation in vivo by reducing lipid peroxides to the respective alcohols thereby stabilizing oxidation products of unsaturated fatty acids. During reticulocyte maturation, lipid peroxidation mediated by 15-lipoxygenase in humans and rabbits and...

Objective: The liver regulates the availability of insulin to other tissues and is the first line insulin response organ physiologically exposed to higher insulin concentrations than the periphery. Basal insulin during fasting inhibits hepatic gluconeogenesis and glycogenolysis, whereas postprandial insulin peaks stimulate glycogen synthesis. The...

Triosephosphate isomerase (TPI) deficiency is a fatal genetic disorder characterized by haemolytic anaemia and neurological dysfunction. Although the enzyme defect in TPI was discovered in the 1960s, the exact etiology of the disease is still debated. Some aspects indicate the disease could be caused by insufficient enzyme activity, whereas other o...

Triosephosphate isomerase (TPI) deficiency is a fatal genetic disorder characterized by haemolytic anaemia and neurological dysfunction. Although the enzyme defect in TPI was discovered in the 1960s, the exact etiology of the disease is still debated. Some aspects indicate the disease could be caused by insufficient enzyme activity, whereas other o...

During an ENU (N-ethyl-N-nitrosourea) mutagenesis screen, we observed a dominant small-eye mutant mouse with viable homozygotes. A corresponding mutant line was established and referred to as Aey69 (abnormality of the eye #69). Comprehensive phenotyping of the homozygous Aey69 mutants in the German Mouse Clinic revealed only a subset of statistical...

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of...

Mutations in the X chromosomal tRNA 2'‑O‑methyltransferase FTSJ1 cause intellectual disability (ID). Although the gene is ubiquitously expressed affected individuals present no consistent clinical features beyond ID. In order to study the pathological mechanism involved in the aetiology of FTSJ1 deficiency-related cognitive impairment, we generated...

Night shift work can have a serious impact on health. Here, we assess whether and how night shift work influences the metabolite profiles, specifically with respect to different chronotype classes. We have recruited 100 women including 68 nurses working both, day shift and night shifts for up to 5 consecutive days and collected 3640 spontaneous uri...

Heterozygous missense mutations in the human VCP gene cause inclusion body myopathy associated with Paget disease of bone and fronto-temporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). The exact molecular mechanisms by which VCP mutations cause disease manifestation in different tissues are incompletely understood. In the present st...

Diabetes mellitus is a group of disorders characterized by prolonged high levels of circulating blood glucose. Type 1 diabetes is caused by decreased insulin production in the pancreas whereas type 2 diabetes may develop due to obesity and lack of exercise; it begins with insulin resistance whereby cells fail to respond properly to insulin and it m...

Urinary analyte data has to be corrected for the sample specific dilution as the dilution varies intra- and interpersonally dramatically, leading to non-comparable concentration measures. Most methods of dilution correction utilized nowadays like probabilistic quotient normalization or total spectra normalization result in a division of the raw dat...

Objective: The worldwide prevalence of obesity has increased to 10% in men and 15% in women and is associated with severe comorbidities such as diabetes, cancer, and cardiovascular disease. Animal models of obesity are central to experimental studies of disease mechanisms and therapeutic strategies. Diet-induced obesity (DIO) models in rodents hav...

Animal welfare requires the adequate housing of animals to ensure health and well-being. The application of environmental enrichment is a way to improve the well-being of laboratory animals. However, it is important to know whether these enrichment items can be incorporated in experimental mouse husbandry without creating a divide between past and...

Raw data of measured parameters (all screens). Raw data are shown as whisker-plots with the box representing 25th percentile, median, and 75th percentile. The length of whiskers is maximally the 1.5-fold interquartile range but is determined by the last value within this range. All individual values and each subgroup are shown. All individual value...

Summary of background lesions in histopathological examination (pathology screen). Affected animals are shown as portion of total examined animals of combined cohorts. (PDF)

Raw data of measured parameters (all screens). (ZIP)

Housing conditions of the 3 experimental groups. (A) “Control” group without any items; (B) group “nest” with 1 cotton nestlet (PLEXX, Article ref. 14010); (C) group “double” with 1 cotton nestlet plus 1 plastic mouse igloo (PLEXX, Article ref. 13100). (PNG)

Results of morphological examination (dysmorphology screen). (PDF)

Results of SHIRPA (neurology screen). Results are presented as number of animals receiving the parameter-specific score in combined cohorts and are described as follows: (x/y/z) with x = number of animals with score “0”; y = number of animals with score “1”; z = number of animals with score “2.” Specifications for scores: body position: 0 = inactiv...

Reduction of animal numbers in single groups or screens. (PDF)

By N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated the mutant mouse line TUB6 that is characterised by severe combined immunodeficiency (SCID) and systemic sterile autoinflammation in homozygotes, and a selective T cell defect in heterozygotes. The causative missense point mutation results in the single amino acid exchange G170W in multicatal...