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

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

Differential Modulation of Beta-Adrenergic Receptor Signaling by Trace Amine-Associated Receptor 1 Agonists

Trace amine-associated receptors (TAAR) are rhodopsin-like G-protein-coupled receptors (GPCR). TAAR are involved in modulation of neuronal, cardiac and vascular functions and they are potentially linked with neurological disorders like schizophrenia and Parkinson's disease. Subtype TAAR1, the best characterized TAAR so far, is promiscuous for a wide set of ligands and is activated by trace amines tyramine (TYR), phenylethylamine (PEA), octopamine (OA), but also by thyronamines, dopamine, and psycho-active drugs. Unfortunately, effects of trace amines on signaling of the two homologous β-adrenergic receptors 1 (ADRB1) and 2 (ADRB2) have not been clarified yet in detail. We, therefore, tested TAAR1 agonists TYR, PEA and OA regarding their effects on ADRB1/2 signaling by co-stimulation studies. Surprisingly, trace amines TYR and PEA are partial allosteric antagonists at ADRB1/2, whereas OA is a partial orthosteric ADRB2-antagonist and ADRB1-agonist. To specify molecular reasons for TAAR1 ligand promiscuity and for observed differences in signaling effects on particular aminergic receptors we compared TAAR, tyramine (TAR) octopamine (OAR), ADRB1/2 and dopamine receptors at the structural level. We found especially for TAAR1 that the remarkable ligand promiscuity is likely based on high amino acid similarity in the ligand-binding region compared with further aminergic receptors. On the other hand few TAAR specific properties in the ligand-binding site might determine differences in ligand-induced effects compared to ADRB1/2. Taken together, this study points to molecular details of TAAR1-ligand promiscuity and identified specific trace amines as allosteric or orthosteric ligands of particular β-adrenergic receptor subtypes

Ein strukturierter Versorgungspfad von der Pädiatrie in die Erwachsenenmedizin für Jugendliche und junge Erwachsene mit einer seltenen Erkrankung

<jats:title>Zusammenfassung</jats:title><jats:p>Die erfolgreiche Organisation und Umsetzung des Übergangs von Jugendlichen und jungen Erwachsenen mit einer chronischen seltenen Erkrankung aus der Pädiatrie in eine Versorgungsform (Transition) und Versorgungsstruktur (Transfer) der Erwachsenenmedizin ist eine wichtige Aufgabe im dezentral aufgebauten deutschen Gesundheitssystem. Ein mittlerweile in der Praxis erprobtes Programm stellt der strukturierte Versorgungspfad des vom Innovationsfonds des gemeinsamen Bundesausschuss (G‑BA) geförderten Konsortiums TRANSLATE-NAMSE dar (Förderkennzeichen 01NVF16024 TRANSLATE-NAMSE). Grundlage des Übergangs in diesem Programm ist der qualitätsgesicherte Informations- und Kompetenztransfer vom pädiatrischen Behandlungsteam zum adoleszenten Patienten, sowie zur neuen Versorgungseinrichtung. Basierend auf einer strukturierten Epikrise und Erhebung des individuellen Beratungsbedarfs erfolgt, ab dem Alter von 16 Jahren, die strukturierte Transitionsschulung des Patienten durch den Pädiater. Nach erfolgreich absolvierten Transfersprechstunden, gemeinsam mit Vertretern der bisherigen pädiatrischen und der zukünftigen erwachsenenmedizinischen Versorgungseinrichtungen, mündet der Prozess in die Übergabe aller notwendigen medizinischen Unterlagen an den Patienten und den Weiterbehandler sowie den Wechsel des Patienten in die neue Versorgungseinrichtung. Eine abschließende Evaluation des Projekts ist für Herbst 2020 geplant.</jats:p&gt

Investigation of Naturally Occurring Single-Nucleotide Variants in Human TAAR1

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 TAAR1 variants in patients with overweight/obesity and disturbed glucose homeostasis. Screening for TAAR1 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 in vitro 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 TAAR1 variants with potential relevance for weight regulation and glucose homeostasis

Ein strukturierter Versorgungspfad von der Pädiatrie in die Erwachsenenmedizin für Jugendliche und junge Erwachsene mit einer seltenen Erkrankung

Die erfolgreiche Organisation und Umsetzung des Übergangs von Jugendlichen und jungen Erwachsenen mit einer chronischen seltenen Erkrankung aus der Pädiatrie in eine Versorgungsform (Transition) und Versorgungsstruktur (Transfer) der Erwachsenenmedizin ist eine wichtige Aufgabe im dezentral aufgebauten deutschen Gesundheitssystem. Ein mittlerweile in der Praxis erprobtes Programm stellt der strukturierte Versorgungspfad des vom Innovationsfonds des gemeinsamen Bundesausschuss (G‑BA) geförderten Konsortiums TRANSLATE-NAMSE dar (Förderkennzeichen 01NVF16024 TRANSLATE-NAMSE). Grundlage des Übergangs in diesem Programm ist der qualitätsgesicherte Informations- und Kompetenztransfer vom pädiatrischen Behandlungsteam zum adoleszenten Patienten, sowie zur neuen Versorgungseinrichtung. Basierend auf einer strukturierten Epikrise und Erhebung des individuellen Beratungsbedarfs erfolgt, ab dem Alter von 16 Jahren, die strukturierte Transitionsschulung des Patienten durch den Pädiater. Nach erfolgreich absolvierten Transfersprechstunden, gemeinsam mit Vertretern der bisherigen pädiatrischen und der zukünftigen erwachsenenmedizinischen Versorgungseinrichtungen, mündet der Prozess in die Übergabe aller notwendigen medizinischen Unterlagen an den Patienten und den Weiterbehandler sowie den Wechsel des Patienten in die neue Versorgungseinrichtung. Eine abschließende Evaluation des Projekts ist für Herbst 2020 geplant.The successful organization and management of the transition and transfer of adolescents and young adults with a chronic rare disease from pediatric to adult care is an important but complex task in the decentralized German healthcare system. The structured transition pathway of the consortium TRANSLATE-NAMSE, funded by the innovation fund of the Federal Joint Committee (G-BA, funding number 01NVF16024 TRANSLATE-NAMSE) is a program that has meanwhile been tested in practice. The main principle of the transition in this program is the quality-assured transfer of information from the pediatric treatment team to the adolescent patient as well as to the healthcare provider(s) of the adult care facility. Based on a structured assessment and documentation of the individual need for information, the transition training is carried out by the pediatric treatment team for adolescent patients aged 16 years and older. In addition, transfer clinics, with the representatives of the previous pediatric and the future adult healthcare providers and the transfer of all necessary medical documentation to the patient and to the new health care provider are part of the program. A final evaluation of the project is expected in late 2020