Publications by authors named "Peter Kühnen"

37 Publications

Natural Autoimmunity to the Thyroid Hormone Monocarboxylate Transporters MCT8 and MCT10.

Biomedicines 2021 Apr 30;9(5). Epub 2021 Apr 30.

Institute for Experimental Endocrinology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, D-10115 Berlin, Germany.

The monocarboxylate transporters 8 (MCT8) and 10 (MCT10) are important for thyroid hormone (TH) uptake and signaling. Reduced TH activity is associated with impaired development, weight gain and discomfort. We hypothesized that autoantibodies (aAb) to MCT8 or MCT10 are prevalent in thyroid disease and obesity. Analytical tests for MCT8-aAb and MCT10-aAb were developed and characterized with commercial antiserum. Serum samples from healthy controls, thyroid patients and young overweight subjects were analyzed, and prevalence of the aAb was compared. MCT8-aAb were additionally tested for biological effects on thyroid hormone uptake in cell culture. Positive MCT8-aAb and MCT10-aAb were detected in all three clinical cohorts analyzed. MCT8-aAb were most prevalent in thyroid patients (11.9%) as compared to healthy controls (3.8%) and overweight adolescents (4.2%). MCT8-aAb positive serum reduced T4 uptake in cell culture in comparison to MCT8-aAb negative control serum. Prevalence of MCT10-aAb was highest in the group of thyroid patients as compared to healthy subjects or overweight adolescents (9.0% versus 4.5% and 6.3%, respectively). We conclude that MCT8 and MCT10 represent autoantigens in humans, and that MCT8-aAb may interfere with regular TH uptake and signaling. The increased prevalence of MCT8-aAb and MCT10-aAb in thyroid disease suggests that their presence may be of pathophysiological relevance. This hypothesis deserves an analysis in large prospective studies.
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http://dx.doi.org/10.3390/biomedicines9050496DOI Listing
April 2021

Gustatory Function Can Improve after Multimodal Lifestyle Intervention: A Longitudinal Observational Study in Pediatric Patients with Obesity.

Child Obes 2021 Mar 1;17(2):136-143. Epub 2021 Feb 1.

Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Obesity is a major health burden in children and adolescents. One influential factor is the choice of food, which is partly determined by gustatory perception. Cross-sectional studies have provided evidence that gustatory function is reduced in patients with obesity compared to individuals with normal weight. This longitudinal study was aimed at investigating potential effects of a multimodal lifestyle intervention program on gustatory function in pediatric patients with obesity. Gustatory perception of five different taste qualities () was assessed in  = 102 patients (age 6-18) with obesity (BMI >97th percentile). Testing was performed before (T0) and after (T1) a residential multimodal weight reduction program between June and December 2015 using well-established taste strips. Overall, identification performance increased between T0 and T1. Patients were most successful at identifying the taste quality at both time points and reached higher scores at identifying and at T1 compared to T0. Moreover, patients rated the highest concentration of significantly at T1 compared to T0. Gustatory function can improve after a multimodal lifestyle intervention program in pediatric patients with obesity. This may lead to a modified choice of food, possibly resulting in a long-term therapeutic success. Therefore, these findings underline the importance of professional nutritional counseling as part of treatment for obesity.
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http://dx.doi.org/10.1089/chi.2020.0318DOI Listing
March 2021

Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials.

Lancet Diabetes Endocrinol 2020 12 30;8(12):960-970. Epub 2020 Oct 30.

Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address:

Background: The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity.

Methods: These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the proportion of participants with at least 10% weight loss compared with baseline at approximately 1 year. A key secondary endpoint was mean percentage change in the most hunger score of the 11-point Likert-type scale at approximately 1 year on the therapeutic dose, which was assessed in a subset of participants aged 12 years or older in the full analysis set who demonstrated at least 5 kg weight loss (or ≥5% in paediatric participants if baseline bodyweight was <100 kg) over the 12-week open-label treatment phase and subsequently proceeded into the placebo-controlled withdrawal sequence, regardless of later disposition. These studies are registered with ClinicalTrials.gov, NCT02896192 and NCT03287960.

Findings: Between Feb 14, 2017, and Sept 7, 2018, ten participants were enrolled in the POMC trial and 11 participants were enrolled in the LEPR trial, and included in the full analysis and safety sets. Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year. The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants. In the LEPR trial, the most commonly reported treatment-related adverse events were injection site reaction in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials.

Interpretation: Our results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency.

Funding: Rhythm Pharmaceuticals.
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http://dx.doi.org/10.1016/S2213-8587(20)30364-8DOI Listing
December 2020

Pharmacological treatment strategies for patients with monogenic obesity.

J Pediatr Endocrinol Metab 2020 Jul 3. Epub 2020 Jul 3.

Institute for Experimental Pediatric Endocrinology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

The leptin melanocortin signaling pathway is playing a pivotal role for body weight regulation. Genetic defects within this cascade are leading to severe hyperphagia and early onset obesity. In most cases, due to persistent hyperphagia the affected patients are not able to stabilize body weight for a longer period of time with conservative treatment strategies based on lifestyle interventions. Therefore, it is of importance to implement alternative treatment options for these patients. This review provides an overview about the published pharmacological treatment attempts in respect to monogenic forms of obesity and summarizes recent research progress about the role of MC4R signaling and POMC derivatives for body weight regulation.
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http://dx.doi.org/10.1515/jpem-2020-0129DOI Listing
July 2020

[Obesity is rarely curable: individual concepts and therapy programs for children and adolescents].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020 Jul;63(7):821-830

Institut für experimentelle pädiatrische Endokrinologie, Charité Universitätsmedizin Berlin, Berlin, Deutschland.

Obesity in children has an increased risk to persist in adulthood. In most cases, obesity starts to develop in children at school age. Lower social economic status and migration background are severe risk factors for obesity. Additionally, genetic predisposition for the development of obesity plays an especially important role in children and adolescents. However, the individual cause for obesity is heterogeneous and complex. This is the reason why only a systematic analysis of individually existing problems is necessary for a differentiated and realistic planning of the treatment. Long-lasting therapy concepts need to be based on current available evidence.The treatment of childhood obesity should rely on multiprofessional lifestyle programs. An exception might be rare monogenic or syndromic forms of obesity, because defects within the central regulatory pathways of body weight regulation could be present. In general, a key component of the treatment strategy should include an improvement of nutrition, physical exercise and self-esteem combined with a reduction of stress. Moreover, the inclusion of parents into the treatment strategy has shown to be beneficial and necessary. Long-term follow-up studies on the development of associated comorbidities are rare. Unfortunately, patient groups at risk are currently not necessarily reached with available treatment programs.A multiprofessional analysis of individual problems and differentiated treatment planning with a participative approach (acknowledging the cultural background and involving members of the family) should lead to long-lasting improvement of the therapeutic outcome. The individual main treatment aim should also include - apart from the reduction of body weight - the improvement of associated comorbidities and quality of life, especially by avoiding any stigmatization. A health-promoting environment is desirable for this salutogenetic approach.
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http://dx.doi.org/10.1007/s00103-020-03164-1DOI Listing
July 2020

Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression.

Thyroid 2020 09 17;30(9):1366-1383. Epub 2020 Apr 17.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, Berlin, Germany.

Mutations of monocarboxylate transporter 8 (MCT8), a thyroid hormone (TH)-specific transmembrane transporter, cause a severe neurodevelopmental disorder, the Allan-Herndon-Dudley syndrome. In MCT8 deficiency, TH is not able to reach those areas of the brain where TH uptake depends on MCT8. Currently, therapeutic options for MCT8-deficient patients are missing, as TH treatment is not successful in improving neurological deficits. Available data on MCT8 protein and transcript levels indicate complex expression patterns in neural tissue depending on species, brain region, sex, and age. However, information on human MCT8 expression is still scattered and additional efforts are needed to map sites of MCT8 expression in neurovascular units and neural tissue. This is of importance because new therapeutic strategies for this disease are urgently needed. To identify regions and time windows of MCT8 expression, we used highly specific antibodies against MCT8 to perform immunofluorescence labeling of postnatal murine brains, adult human brain tissue, and human cerebral organoids. Qualitative and quantitative analyses of murine brain samples revealed stable levels of MCT8 protein expression in endothelial cells of the bloodbrain barrier (BBB), choroid plexus epithelial cells, and tanycytes during postnatal development. Conversely, the neuronal MCT8 protein expression that was robustly detectable in specific brain regions of young mice strongly declined with age. Similarly, MCT8 immunoreactivity in adult human brain tissue was largely confined to endothelial cells of the BBB. Recently, cerebral organoids emerged as promising models of human neural development and our first analyses of forebrain-like organoids revealed MCT8 expression in early neuronal progenitor cell populations. With respect to MCT8-deficient conditions, our analyses not only strongly support the contention that the BBB presents a lifelong barrier to TH uptake but also highlight the need to decipher the TH transport role of MCT8 in early neuronal cell populations in more detail. Improving the understanding of the spatiotemporal expression in latter barriers will be critical for therapeutic strategies addressing MCT8 deficiency in the future.
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http://dx.doi.org/10.1089/thy.2019.0544DOI Listing
September 2020

Differential Signaling Profiles of MC4R Mutations with Three Different Ligands.

Int J Mol Sci 2020 Feb 12;21(4). Epub 2020 Feb 12.

Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, D-10117 Berlin, Germany.

The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin-melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via G-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations between the different signaling pathways, we investigated three major mutations: a G loss-of-function (S127L) and a G gain-of-function mutant (H158R), as well as the most common European single nucleotide polymorphism (V103I). We tested signaling of all four major G protein families plus extracellular regulated kinase (ERK) phosphorylation and β-arrestin2 recruitment, using the two endogenous agonists, α- and β-melanocyte stimulating hormone (MSH), along with a synthetic peptide agonist (NDP-α-MSH). The S127L mutation led to a full loss-of-function in all investigated pathways, whereas V103I and H158R were clearly biased towards the G pathway when challenged with the endogenous ligands. These results show that mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.
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http://dx.doi.org/10.3390/ijms21041224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072973PMC
February 2020

Antagonistic Autoantibodies to Insulin-Like Growth Factor-1 Receptor Associate with Poor Physical Strength.

Int J Mol Sci 2020 Jan 11;21(2). Epub 2020 Jan 11.

Institute for Experimental Endocrinology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, D-13353 Berlin, Germany.

Natural autoantibodies to the IGF1 receptor (IGF1R-aAb) have been described in relation to Graves' ophthalmopathy. Other physiological roles of natural IGF1R-aAb are not known. We hypothesized that IGF1R-aAb may be related to muscle development. Serum samples ( = 408) from young overweight subjects ( = 143) were collected during a lifestyle intervention study. Anthropometric parameters, along with leptin, IGF1 and IGF1R-aAb concentrations, were analyzed, and the subjects were categorized into positive or negative for IGF1R-aAb. Eleven out of 143 subjects (7.7%) were positive for IGF1R-aAb. Identified IGF1R-aAb were molecularly characterized and showed antagonistic activity in vitro impairing IGF1-mediated IGF1R activation. Mean body weight, height or age were similar between IGF1R-aAb-positive and -negative subjects, but IGF1 concentrations differed. Jumping ability, as well as right and left handgrip strengths, were lower in the IGF1R-aAb-positive as compared to the IGF1R-aAb-negative subjects. We conclude that natural IGF1R-aAb are detectable in apparently healthy subjects and are capable of antagonizing IGF1-dependent IGF1R activation. Moreover, the presence of IGF1R-aAb is associated with poor physical strength. Although the causality of this association is unclear, the data imply a potential influence of IGF1R autoimmunity on muscle development.
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http://dx.doi.org/10.3390/ijms21020463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013472PMC
January 2020

Tissue Sodium Content and Arterial Hypertension in Obese Adolescents.

J Clin Med 2019 Nov 21;8(12). Epub 2019 Nov 21.

Institute for Computational and Imaging Science in Cardiovascular Medicine, Charité - Universitätsmedizin 13353 Berlin, Germany.

Early-onset obesity is known to culminate in type 2 diabetes, arterial hypertension and subsequent cardiovascular disease. The role of sodium (Na) homeostasis in this process is incompletely understood, yet correlations between Na accumulation and hypertension have been observed in adults. We aimed to investigate these associations in adolescents. A cohort of 32 adolescents (13-17 years), comprising 20 obese patients, of whom 11 were hypertensive, as well as 12 age-matched controls, underwent Na-MRI of the left lower leg with a standard clinical 3T scanner. Median triceps surae muscle Na content in hypertensive obese (11.95 mmol/L [interquartile range 11.62-13.66]) was significantly lower than in normotensive obese (13.63 mmol/L [12.97-17.64]; = 0.043) or controls (15.37 mmol/L [14.12-16.08]; = 0.012). No significant differences were found between normotensive obese and controls. Skin Na content in hypertensive obese (13.33 mmol/L [11.53-14.22] did not differ to normotensive obese (14.12 mmol/L [13.15-15.83]) or controls (11.48 mmol/L [10.48-12.80]), whereas normotensive obese had higher values compared to controls ( = 0.004). Arterial hypertension in obese adolescents is associated with low muscle Na content. These findings suggest an early dysregulation of Na homeostasis in cardiometabolic disease. Further research is needed to determine whether this association is causal and how it evolves in the transition to adulthood.
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http://dx.doi.org/10.3390/jcm8122036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947559PMC
November 2019

Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective.

Front Endocrinol (Lausanne) 2019 31;10:515. Epub 2019 Jul 31.

Group Protein X-ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

The melanocortin-4 receptor (MC4R) can be endogenously activated by binding of melanocyte-stimulating hormones (MSH), which mediates anorexigenic effects. In contrast, the agouti-related peptide (AgRP) acts as an endogenous inverse agonist and suppresses ligand-independent basal signaling activity (orexigenic effects). Binding of ligands to MC4R leads to the activation of different G-protein subtypes or arrestin and concomitant signaling pathways. This receptor is a key protein in the hypothalamic regulation of food intake and energy expenditure and naturally-occurring inactivating variants are the most frequent cause of monogenic obesity. In general, obesity is a growing problem on a global scale and is of social, medical, and economic relevance. A significant goal is to develop optimized pharmacological tools targeting MC4R without adverse effects. To date, this has not been achieved because of non-selective ligands across the five functionally different MCR subtypes (MC1-5R). This motivates further investigation of (i) the three-dimensional MC4R structure, (ii) binding mechanisms of various ligands, and (iii) the molecular transfer process of signal transduction, with the aim of understanding how structural features are linked with functional-physiological aspects. Unfortunately, experimentally elucidated structural information is not yet available for the MC receptors, a group of class A G-protein coupled receptors (GPCRs). We, therefore, generated MC4R homology models and complexes with interacting partners to describe approximate structural properties associated with signaling mechanisms. In addition, molecular insights from pathogenic mutations were incorporated to discriminate more precisely their individual malfunction of the signal transfer mechanism.
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http://dx.doi.org/10.3389/fendo.2019.00515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685040PMC
July 2019

Evaluation of a rare glucose-dependent insulinotropic polypeptide receptor variant in a patient with diabetes.

Diabetes Obes Metab 2019 05 19;21(5):1168-1176. Epub 2019 Feb 19.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Institute of Experimental Pediatric Endocrinology, Berlin, Germany.

Aims: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that augments insulin secretion in pancreatic β-cells via its glucose-dependent insulinotropic polypeptide receptor (GIPR). Recent genome-wide association studies identified a single nucleotide variant (SNV) in the GIPR encoding gene (GIPR), rs1800437, that is associated with obesity and insulin resistance. In the present study, we tested whether GIPR variants contribute to obesity and disturb glucose homeostasis or diabetes in specific patient populations.

Materials And Methods: Exon sequencing of GIPR was performed in 164 children with obesity and insulin resistance and in 80 children with paediatric-onset diabetes of unknown origin. The Study of Health in Pomerania (SHIP) cohort, comprising 8320 adults, was screened for the GIPR variant Arg217Leu. GIPR variants were expressed in COS-7 cells and cAMP production was measured upon stimulation with GIP. Cell surface expression was determined by ELISA. Protein homology modelling of the GIPR variants was performed to extract three-dimensional information of the receptor.

Results: A heterozygous missense GIPR variant Arg217Leu (rs200485112) was identified in a patient of Asian ancestry. Functional characterization of Arg217Leu revealed reduced surface expression and signalling after GIP challenge. The homology model of the GIPR structure supports the observed functional relevance of Arg217Leu.

Conclusion: In vitro functional studies and protein homology modelling indicate a potential relevance of the GIPR variant Arg217Leu in receptor function. The heterozygous variant displayed partial co-segregation with diabetes. Based on these findings, we suggest that GIPR variants may play a role in disturbed glucose homeostasis and may be of clinical relevance in homozygous patients.
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http://dx.doi.org/10.1111/dom.13634DOI Listing
May 2019

Sleep Timing in Patients with Precocious and Delayed Pubertal Development.

Clocks Sleep 2019 Mar 16;1(1):140-150. Epub 2019 Feb 16.

Institute for Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany.

Previous studies have reported a shift in the timing of sleep during adolescence toward a later time. To date, it is unclear whether hormonal changes during puberty might contribute to this change in sleeping behavior. We systematically assessed pubertal development and sleep timing in a cross-sectional case-control study in girls with precocious ( = 42) and boys with delayed pubertal development ( = 19). We used the Munich ChronoType Questionnaire and the Children's ChronoType Questionnaire to assess sleep timing in patients and age- and sex-matched controls ( = 309) and used the midpoint of sleep on free days, corrected for potential sleep debt accumulated during the school week, as a marker for sleep timing. Compared to the controls, girls with central precocious puberty showed a delay in sleep timing of 54 min, and girls with premature pubarche slept on average 30 min later. Male adolescents with delayed pubertal development showed an average sleep midpoint that was 40 min earlier compared to the control group. The results of this pilot study suggest an association between pubertal onset and shifts in sleep timing, which is a novel finding in human sleep behavior. Prospective studies in larger cohorts will be needed to examine the robustness and generalizability of the findings.
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http://dx.doi.org/10.3390/clockssleep1010013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509672PMC
March 2019

Melanocortin-4 Receptor Signalling: Importance for Weight Regulation and Obesity Treatment.

Trends Mol Med 2019 02 11;25(2):136-148. Epub 2019 Jan 11.

Institute for Experimental Pediatric Endocrinology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.

The melanocortin-4 receptor (MC4R) - embedded in the leptin-melanocortin pathway - is activated by proopiomelanocortin (POMC)-derived neuropeptides such as α- and β-melanocyte-stimulating hormone (MSH) and plays an important role in hypothalamic body-weight regulation. Accordingly, MC4R is a potential drug target to combat obesity. Previous attempts to develop MC4R agonists failed due to ineffectiveness or severe adverse events. Recently, a new generation of MC4R ligands was developed. Specifically, setmelanotide was found to be effective by inducing biased signalling of the MC4R and thereby reducing feelings of hunger and leading to substantial weight loss in patients with POMC or leptin receptor deficiency. This new potential pharmacological treatment option could be beneficial for further groups of obese patients with defects in the leptin-melanocortin signalling pathway.
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http://dx.doi.org/10.1016/j.molmed.2018.12.002DOI Listing
February 2019

An Integrated Understanding of the Molecular Mechanisms of How Adipose Tissue Metabolism Affects Long-term Body Weight Maintenance.

Diabetes 2019 01 2;68(1):57-65. Epub 2018 Nov 2.

Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Lifestyle-based weight loss interventions frequently demonstrate long-term inefficiency and weight regain. Identification of underlying mechanisms and predictors to identify subjects who will benefit from lifestyle-based weight loss strategies is urgently required. We analyzed 143 adults of the randomized Maintain trial (Maintain-Adults) after intended weight loss to identify mechanisms contributing to the regulation of body weight maintenance. Unbiased RNA sequencing of adipose and skeletal muscle biopsies revealed fatty acid metabolism as a key pathway modified by weight loss. Variability of key enzymes of this pathway, estimates of substrate oxidation, and specific serum acylcarnitine (AC) species, representing a systemic snapshot of in vivo substrate flux, predicted body weight maintenance (defined as continuous or dichotomized [< or ≥3% weight regain] variable) 18 months after intended weight loss in the entire cohort. Key results were confirmed in a similar randomized controlled trial in 137 children and adolescents (Maintain-Children), which investigated the same paradigm in a pediatric cohort. These data suggest that adaption of lipid utilization in response to negative energy balance contributes to subsequent weight maintenance. Particularly a functional role for circulating ACs, which have been suggested to reflect intracellular substrate utilization, as mediators between peripheral energy stores and control of long-term energy homeostasis was indicated.
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http://dx.doi.org/10.2337/db18-0440DOI Listing
January 2019

MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency.

Nat Med 2018 05 7;24(5):551-555. Epub 2018 May 7.

Institute for Experimental Pediatric Endocrinology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.
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http://dx.doi.org/10.1038/s41591-018-0015-9DOI Listing
May 2018

Mean High-Dose l-Thyroxine Treatment Is Efficient and Safe to Achieve a Normal IQ in Young Adult Patients With Congenital Hypothyroidism.

J Clin Endocrinol Metab 2018 04;103(4):1459-1469

Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, Berlin, Germany.

Context: The optimal levothyroxine (LT4) dose to treat congenital hypothyroidism (CH) remains unclear, with debate over whether higher starting doses (>10 µg/kg) are necessary and safe for a normal intelligence quotient (IQ).

Objective: To examine psychomotor, metabolic, and quality of life (QoL) outcomes in patients with CH treated with a mean high initial LT4 dose.

Design, Settings, Participants: A cross-sectional cohort study of patients with CH identified in the Berlin newborn screening program from 1979 to 2003; 76 patients with CH (mean age, 18 years; mean initial LT4 dose, 13.5 µg/kg) and 40 siblings completed the study.

Main Outcome Measures: Psychomotor (Wechsler Intelligence Test, CNS Vital Signs), QoL (short form-36 Health Survey), anthropometric (body mass index, height), and metabolic (intima media thickness, laboratory parameters) outcomes were compared with those of healthy siblings. Mean values and percentage of episodes of elevated thyroxine (T4) and tri-jod-thyronin (T3) and suppressed thyrotropin (TSH) before age 2 years were analyzed. A meta-analysis of CH treatment studies was performed.

Results: There were no significant differences in IQ, QoL, or other outcome measures in patients with CH compared with controls. Most T4 levels were high before age 2 years and during subsequent testing, but mean T3 and TSH levels remained normal. The meta-analysis showed a significant IQ difference in severe vs mild CH cases only when treatment started with an LT4 dose <10 µg/kg.

Conclusions: High initial LT4 dosing was effective and safely achieved optimal cognitive development in patients with CH, including those severely affected. Supranormal T4 values during infancy were not associated with impaired IQ in adolescence.
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http://dx.doi.org/10.1210/jc.2017-01937DOI Listing
April 2018

Investigation of Naturally Occurring Single-Nucleotide Variants in Human TAAR1.

Front Pharmacol 2017 24;8:807. Epub 2017 Nov 24.

Institute of Experimental Pediatric Endocrinology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universitt zu Berlin, Berlin, Germany.

Activation of trace amine-associated receptor 1 (TAAR1) in endocrine pancreas is involved in weight regulation and glucose homeostasis. The purpose of this study was the identification and characterization of potential variants in patients with overweight/obesity and disturbed glucose homeostasis. Screening for variants was performed in 314 obese or overweight patients with impaired insulin secretion. The detected variants were functionally characterized concerning TAAR1 cell surface expression and signaling properties and their allele frequencies were determined in the population-based Study of Health in Pomerania (SHIP). Three heterozygous carriers of the single nucleotide missense variants p.Arg23Cys (R23C, rs8192618), p.Ser49Leu (S49L, rs140960896), and p.Ille171Leu (I171L, rs200795344) were detected in the patient cohort. While p.Ser49Leu and p.Ille171Leu were found in obese/overweight patients with slightly impaired glucose homeostasis, p.Arg23Cys was identified in a patient with a complete loss of insulin production. Functional characterization revealed a like wild-type function for I171L, partial loss of function for S49L and a complete loss of function for R23C. The frequency of the R23C variant in 2018 non-diabetic control individuals aged 60 years and older in the general population-based SHIP cohort was lower than in the analyzed patient sample. Both variants are rare in the general population indicating a recent origin in the general gene pool and/or the consequence of pronounced purifying selection, in line with the obvious detrimental effect of the mutations. In conclusion, our study provides hints for the existence of naturally occurring variants with potential relevance for weight regulation and glucose homeostasis.
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http://dx.doi.org/10.3389/fphar.2017.00807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705543PMC
November 2017

Primary sulphonylurea therapy in a newborn with transient neonatal diabetes attributable to a paternal uniparental disomy 6q24 (UPD6).

Diabetes Obes Metab 2018 02 5;20(2):474-475. Epub 2017 Oct 5.

Institute of Experimental Pediatric Endocrinology, Charité University Medicine Berlin, Berlin, Germany.

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http://dx.doi.org/10.1111/dom.13085DOI Listing
February 2018

Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans.

J Clin Invest 2017 May 27;127(5):1700-1713. Epub 2017 Mar 27.

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.
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http://dx.doi.org/10.1172/JCI91913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409795PMC
May 2017

Trace element and cytokine concentrations in patients with Fibrodysplasia Ossificans Progressiva (FOP): A case control study.

J Trace Elem Med Biol 2017 Jan 4;39:186-192. Epub 2016 Oct 4.

Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Germany. Electronic address:

Fibrodysplasia Ossificans Progressiva (FOP) is a rare inherited disease characterized by progressive heterotopic ossification. Disease onset, severity and symptoms vary between FOP patients, as does the frequency and activity of so-called flare-ups, during which tendons, ligaments, muscle and soft tissue are replaced by bone. Traumata, infections or other stressors are known inducers of flare-ups, and the hormone Activin A may be involved in disease activity; however, reliable biomarkers for FOP activity are missing, and the basal trace element and inflammatory state of patients are unknown. We hypothesized that FOP patients develop characteristic deficiencies in inflammation-related trace elements and display a chronically increased inflammatory cytokine level, collectively aggravating disease course and flare-up risk. Serum samples from 15 FOP patients and 25 relatives were collected under highest quality standards. Concentrations of Cu, Se and Zn were determined by total reflection X-ray fluorescence, and 27 cytokines along with Activin A by specific antibody-based techniques. Data were tested for normal distribution and analyzed by parametric or non-parametric tests. Concentrations of Se and Cu were not different between the groups, while Zn levels were slightly higher in FOP as compared to controls (1110±251 vs. 970±176ng/ml, P=0.04). The average concentrations of cytokines and Activin A were not different. When focusing on the two patients with self-reported flare-ups, again no obvious differences were noted. The cytokines Eotaxin, G-CSF, hbFGF and TNF-α were within the upper half of measured concentrations, and may warrant further longitudinal analyses. Our data do not support the hypothesis that FOP patients display a characteristic pattern of trace elements or have a generally increased tone of pro-inflammatory cytokines.
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http://dx.doi.org/10.1016/j.jtemb.2016.10.001DOI Listing
January 2017

Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity.

Cell Metab 2016 09 25;24(3):502-509. Epub 2016 Aug 25.

Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.

The estimated heritability of human BMI is close to 75%, but identified genetic variants explain only a small fraction of interindividual body-weight variation. Inherited epigenetic variants identified in mouse models named "metastable epialleles" could in principle explain this "missing heritability." We provide evidence that methylation in a variably methylated region (VMR) in the pro-opiomelanocortin gene (POMC), particularly in postmortem human laser-microdissected melanocyte-stimulating hormone (MSH)-positive neurons, is strongly associated with individual BMI. Using cohorts from different ethnic backgrounds, including a Gambian cohort, we found evidence suggesting that methylation of the POMC VMR is established in the early embryo and that offspring methylation correlates with the paternal somatic methylation pattern. Furthermore, it is associated with levels of maternal one-carbon metabolites at conception and stable during postnatal life. Together, these data suggest that the POMC VMR may be a human metastable epiallele that influences body-weight regulation.
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http://dx.doi.org/10.1016/j.cmet.2016.08.001DOI Listing
September 2016

Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist.

N Engl J Med 2016 Jul;375(3):240-6

From the Institute for Experimental Pediatric Endocrinology (P.K., O.B., H.K.), the Department of Pediatric Endocrinology and Diabetes (S.W., A.G.), the Department of Endocrinology, Diabetes, and Nutrition and Charité Center for Cardiovascular Research (K.M.), and the Department of Dermatology and Allergy, Clinical Research Center for Hair and Skin Science (U.B.-P.), Charité-Universitätsmedizin Berlin, and the Clinical Research Unit, Berlin Institute of Health (K.M.) - all in Berlin; the Institute of Cardiometabolism and Nutrition, Assistance Publique-Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, INSERM-Sorbonne University, Université Pierre et Marie Curie, Unité Mixte de Recherche Scientifique 1166, Paris (K.C., L.L.M.); and Rhythm Pharmaceuticals, Boston (K.G.).

Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).
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http://dx.doi.org/10.1056/NEJMoa1512693DOI Listing
July 2016

Detection of Novel Gene Variants Associated with Congenital Hypothyroidism in a Finnish Patient Cohort.

Thyroid 2016 09 2;26(9):1215-24. Epub 2016 Aug 2.

1 Department of Physiology, Institute of Biomedicine, University of Turku , Turku, Finland .

Background: Congenital hypothyroidism (CH) is defined as the lack of thyroid hormones at birth. Mutations in at least 15 different genes have been associated with this disease. While up to 20% of CH cases are hereditary, the majority of cases are sporadic with unknown etiology. Apart from a monogenic pattern of inheritance, multigenic mechanisms have been suggested to play a role in CH. The genetics of CH has not been studied in Finland so far. Therefore, multigenic sequencing of CH candidate genes was performed in a Finnish patient cohort with both familial and sporadic CH.

Methods: A targeted next-generation sequencing (NGS) panel, covering all exons of the major CH genes, was applied for 15 patients with sporadic and 11 index cases with familial CH.

Results: Among the familial cases, six pathogenic mutations were found in the TPO, PAX8, and TSHR genes. Furthermore, pathogenic NKX2.1 and TG mutations were identified from sporadic cases, together with likely pathogenic variants in the TG, NKX2.5, SLC26A4, and DUOX2 genes. All identified novel pathogenic mutations were confirmed by Sanger-sequencing and characterized in silico and/or in vitro.

Conclusion: In summary, the CH panel provides an efficient, cost-effective, and multigenic screening tool for both known and novel CH gene mutations. Hence, it may be a useful method to identify accurately the genetic etiology for dyshormogenic, familial, or syndromic forms of CH.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036323PMC
http://dx.doi.org/10.1089/thy.2016.0016DOI Listing
September 2016

Generation of integration free induced pluripotent stem cells from fibrodysplasia ossificans progressiva (FOP) patients from urine samples.

Stem Cell Res 2016 Jan 1;16(1):54-8. Epub 2015 Dec 1.

Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Föhrer Strasse 15, 13353 Berlin, Germany; Berlin Institute of Health-Stem Cell Core Facility, Berlin, Germany.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare, autosomal dominant transmitted genetic disease. Patients experience progressive bone formation replacing tendons, ligaments, muscle and soft tissue. Cause of FOP are gain-of-function mutations in the Bone Morphogenetic Protein (BMP) receptor Activin A receptor type 1 (ACVR1) (Kaplan et al., 2008). The most common mutation is R206H, which leads to the substitution of codon 206 from arginine to histidine (Shore et al., 2006). Here, we describe the derivation and characterization of two hiPSC lines from two FOP patients, both carrying the mutation R206H. Cells were isolated from urine and reprogrammed using integration free Sendai virus vectors under defined conditions.
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http://dx.doi.org/10.1016/j.scr.2015.11.017DOI Listing
January 2016

Positive correlation of thyroid hormones and serum copper in children with congenital hypothyroidism.

J Trace Elem Med Biol 2016 Sep 24;37:90-95. Epub 2016 May 24.

Institute for Experimental Endocrinology, Charité -Universitaetsmedizin Berlin, D-13353 Berlin, Germany. Electronic address:

Thyroid hormones are of central relevance for growth and development. However, the underlying molecular mechanisms are still not fully understood. Recent studies in humans and mice have demonstrated that serum levels of selenium (Se) and copper (Cu) are positively affected by thyroid hormones. Given the importance of these trace elements for many biochemical processes, we tested whether this interaction is found in children at risk for hypothyroidism, potentially providing a novel factor contributing to the disturbed development observed in congenital hypothyroidism (CH). We conducted a cross-sectional analysis of 84 children diagnosed with CH displaying a wide range of thyroid hormone concentrations. Serum Se and Cu concentrations were measured by total reflection X-ray fluorescence. Data for thyrotropin (TSH) were available in all, thyroxine (T4) and free thyroxine (fT4) in the majority and triiodothyronine (T3) in 29 of the children. Spearman rank analyzes were performed. Cu and thyroid hormones showed a strong positive correlation (Cu/T4, rho=0.5241, P=0.0003; Cu/T3, rho=0.6003, P=0.0006). Unlike in adults, no associations were found between Se and any of the thyroid hormones. Our data highlight that serum Cu and thyroid hormones are strongly associated already in early postnatal life. Severely hypothyroid children are thus at risk of developing a Cu deficiency if not adequately nourished or supplemented. This finding needs to be verified in larger groups of children in order not to miss an easily-avoidable risk factor for poor development.
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http://dx.doi.org/10.1016/j.jtemb.2016.05.007DOI Listing
September 2016

Role of (68)Ga somatostatin receptor PET/CT in the detection of endogenous hyperinsulinaemic focus: an explorative study.

Eur J Nucl Med Mol Imaging 2016 Aug 29;43(9):1593-600. Epub 2016 Feb 29.

Institute for Experimental Paediatric Endocrinology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.

Purpose: To explore the role of (68)Ga-DOTATATE/DOTATOC PET/CT (SR PET/CT) in patients with suspicion of or histopathologically proven pancreatogenic hyperinsulinaemic hypoglycaemia.

Methods: We included 13 patients with histopathologically proven or a high clinical suspicion of pancreatogenic hyperinsulinaemia. All the patients underwent a SR PET/CT scan. The results were correlated with histopathological findings. Normalization of blood glucose levels after resection of the pancreatic lesion, as well as a cytological and/or pathological diagnosis of insulinoma, was considered the diagnostic gold standard for insulinoma. The diagnosis of nesidioblastosis was based on exclusion of an insulinoma and conclusive pathological examination of a segment of the pancreas. Malignant insulinoma was defined as the presence of locoregional or distant metastases.

Results: Based on histopathology, 13 patients were found to have pancreatic hyperinsulinaemia: two patients had malignant insulinoma, eight had nonmetastasized insulinoma, and three had nesidioblastosis. SR PET was positive in 11 of the 13 patients (84.6 %) with a final diagnosis of endogenous pancreatic hypoglycaemia. Histopathological staining confirmed 16 foci of hyperinsulinism (insulin positivity). SR PET detected 14 of the 16 lesions, resulting in a sensitivity of 87 %. One intrapancreatic spleen was falsely diagnosed as insulinoma focus on SR PET, resulting in positive predictive value of 93.3 %. Immunohistochemical staining of somatostatin receptor (SSR) subtype 2a was available in ten specimens: two nesidioblastosis, and seven benign and one malignant insulinoma. Eight out of the ten specimens (80 %) stained strongly to moderately positive. Seven of the eight SSR2a-positive lesions were picked up on SR PET. Based on the results of SR PET/CT, nine patients achieved complete remission of the hypoglycaemic events during follow-up.

Conclusion: This explorative study suggests that SR PET in combination with CT may play a significant role in the detection and management of patients with pancreatogenic hyperinsulinaemic hypoglycaemia. A large proportion of insulinomas express SSR2a, and a larger study is needed to fully assess the diagnostic accuracy of SR PET in patients with insulinoma and nesidioblastosis compared with current localizing studies used in clinical practice.
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http://dx.doi.org/10.1007/s00259-016-3331-7DOI Listing
August 2016

Treatment of congenital thyroid dysfunction: Achievements and challenges.

Best Pract Res Clin Endocrinol Metab 2015 Jun 26;29(3):399-413. Epub 2015 Apr 26.

Institute for Experimental Paediatric Endocrinology, Charite, University-Medicine-Berlin, Augustenburgerplatz 1, D-13353 Berlin, Germany.

The active thyroid hormone tri-iodothyronine (T3) is essential for a normal development of children. Especially within the first years of life, thyroid hormone is pivotal in enabling maturation of complex brain function and somatic growth. The most compelling example for a life without thyroid hormone are those historical cases of children who came to birth without a thyroid gland - as shown in autopsy-studies- and who suffered from untreated hypothyroidism, at that time initially called "sporadic congenital hypothyroidism" (CH). In the last decades huge achievements resulted in a normal development of these children based on newborn screening programs that enable an early onset of a high dose LT4-treatment. Further progress will be necessary to further tailor an individualized thyroid hormone substitution approach and to identify those more complex patients with congenital hypothyroidism and associated defects, who will not benefit from an even optimized LT4 therapy. Besides the primary production of thyroid hormone a variety of further mechanisms are necessary to mediate the function of T3 on normal development that are located downstream of thyroid hormone production. Abnormalities of these mechanisms include the MCT8-transport defect, deiodinase-insufficiency and thyroid hormone receptor alpha-and beta defects. These thyroid hormone resistant diseases can not be treated with classical LT4 substitution alone. The development of new treatment options for those rare cases of thyroid hormone resistance is one of the most challenging tasks in the field of congenital thyroid diseases today.
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http://dx.doi.org/10.1016/j.beem.2015.04.004DOI Listing
June 2015

Modulation of monocarboxylate transporter 8 oligomerization by specific pathogenic mutations.

J Mol Endocrinol 2015 Feb;54(1):39-50

Institut für Experimentelle Pädiatrische EndokrinologieCharité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyLeibniz-Institut für Molekulare PharmakologieBerlin, GermanyUniversitätsklinikum EssenKlinik für Endokrinologie und Stoffwechselerkrankungen, Essen, GermanyJacobs University BremenBremen, Germany

The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS). These membrane-spanning proteins facilitate translocation of a variety of substrates, MCT8 specifically transports iodothyronines. Mutations in MCT8 are the underlying cause of severe X-linked psychomotor retardation. At the molecular level, such mutations led to deficiencies in substrate translocation due to reduced cell-surface expression, impaired substrate binding, or decreased substrate translocation capabilities. However, the causal relationships between genotypes, molecular features of mutated MCT8, and patient characteristics have not yet been comprehensively deciphered. We investigated the relationship between pathogenic mutants of MCT8 and their capacity to form dimers (presumably oligomeric structures) as a potential regulatory parameter of the transport function of MCT8. Fourteen pathogenic variants of MCT8 were investigated in vitro with respect to their capacity to form oligomers. Particular mutations close to the substrate translocation channel (S194F, A224T, L434W, and R445C) were found to inhibit dimerization of MCT8. This finding is in contrast to those for other transporters or transmembrane proteins, in which substitutions predominantly at the outer-surface inhibit oligomerization. Moreover, specific mutations of MCT8 located in transmembrane helix 2 (del230F, V235M, and ins236V) increased the capacity of MCT8 variants to dimerize. We analyzed the localization of MCT8 dimers in a cellular context, demonstrating differences in MCT8 dimer formation and distribution. In summary, our results add a new link between the functions (substrate transport) and protein organization (dimerization) of MCT8, and might be of relevance for other members of the MFS. Finally, the findings are discussed in relationship to functional data combined with structural-mechanistical insights into MCT8.
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http://dx.doi.org/10.1530/JME-14-0272DOI Listing
February 2015

Recessive mutations in PCBD1 cause a new type of early-onset diabetes.

Diabetes 2014 Oct 21;63(10):3557-64. Epub 2014 May 21.

Experimental and Clinical Research Center, Charité Medical Faculty and Max-Delbrück Center for Molecular Medicine, Berlin, Germany

Mutations in several genes cause nonautoimmune diabetes, but numerous patients still have unclear genetic defects, hampering our understanding of the development of the disease and preventing pathogenesis-oriented treatment. We used whole-genome sequencing with linkage analysis to study a consanguineous family with early-onset antibody-negative diabetes and identified a novel deletion in PCBD1 (pterin-4 α-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 α), a gene that was recently proposed as a likely cause of diabetes. A subsequent reevaluation of patients with mild neonatal hyperphenylalaninemia due to mutations in PCBD1 from the BIODEF database identified three additional patients who had developed HNF1A-like diabetes in puberty, indicating early β-cell failure. We found that Pcbd1 is expressed in the developing pancreas of both mouse and Xenopus embryos from early specification onward showing colocalization with insulin. Importantly, a morpholino-mediated knockdown in Xenopus revealed that pcbd1 activity is required for the proper establishment of early pancreatic fate within the endoderm. We provide the first genetic evidence that PCBD1 mutations can cause early-onset nonautoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. This condition responds to and can be treated with oral drugs instead of insulin, which is important clinical information for these patients. Finally, patients at risk can be detected through a newborn screening for phenylketonuria.
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http://dx.doi.org/10.2337/db13-1784DOI Listing
October 2014

Occurrence of giant focal forms of congenital hyperinsulinism with incorrect visualization by (18) F DOPA-PET/CT scanning.

Clin Endocrinol (Oxf) 2014 Dec 19;81(6):847-54. Epub 2014 May 19.

Institut für experimentelle pädiatrische Endokrinologie, Charité Universitätsmedizin, Berlin, Germany.

Context: Congenital hyperinsulinism (CHI) is a rare disease characterized by severe hypoglycaemic episodes due to pathologically increased insulin secretion from the pancreatic beta cells. When untreated, CHI might result in irreversible brain damage and death. Currently, two major subtypes of CHI are known: a focal form, associated with local distribution of affected beta cells and a nonfocal form, affecting every single beta cell. The identification of focal forms is important, as the patients can be cured by limited surgery. (18) F DOPA-PET/CT is an established non-invasive approach to differentiate focal from nonfocal CHI.

Objective: The purpose of this study was to identify possible limitations of (18) F DOPA-PET/CT scan in patients with focal forms nonfocal CHI.

Design: A retrospective chart review of 32 patients (from 2008 through 2013) who underwent (18) F DOPA-PET/CT and partial pancreatectomy for focal CHI at the reference centres in Berlin, Germany and London, UK.

Results: In most cases (n = 29, 90·7%), (18) F DOPA-PET/CT was sufficient to localize the complete focal lesion. However, in some patients (n = 3, 9·3%), (18) F DOPA-PET/CT wrongly visualized only a small portion of the focal lesion. In this group of patients, a so-called 'giant focus' was detected in histopathological analysis during the surgery.

Conclusions: Our data show that in most patients with focal CHI (18) F DOPA-PET/CT correctly predicts the size and anatomical localisation of the lesion. However, in those patients with a 'giant focal' lesion (18) F DOPA-PET/CT is unreliable for correct identification of 'giant focus' cases.
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http://dx.doi.org/10.1111/cen.12473DOI Listing
December 2014