The different faces of GATA2 deficiency: implications for therapy and surveillance

GATA2 deficiency is one of the most common genetic predispositions to pediatric myelodysplastic syndrome (MDS) in children and adolescents. The wide spectrum of disease comprises, among others, hematological, immunological and pulmonary manifestations, as well as occasionally distinct organ anomalies. Due to the elevated risk of progression, nearly all individuals with GATA2-related MDS eventually undergo a hematopoietic stem cell transplantation (HSCT) at some point in their lives. Nevertheless, the optimal timing, method, and even the indication for HSCT in certain cases are still matter of debate and warrant further research. In this article, we report five patients with different hematological and immunological manifestations of GATA2 deficiency ranging from immunodeficiency and refractory cytopenia of childhood without chromosomal aberrations to relapsed MDS-related acute myeloid leukemia. We discuss the adopted strategies, including intensity of surveillance, indication and timing of HSCT, based on morphological, clinical and molecular markers, as well as individual patient needs. We conclude that a better characterization of the natural disease course, a better understanding of the prognostic significance of somatic aberrations and a thorough evaluation of patients´ perspectives and preferences are required to achieve a personalized approach aimed at improving the care of these patients

An intact ribose moiety at A2602 of 23S rRNA is key to trigger peptidyl-tRNA hydrolysis during translation termination

Peptide bond formation and peptidyl-tRNA hydrolysis are the two elementary chemical reactions of protein synthesis catalyzed by the ribosomal peptidyl transferase ribozyme. Due to the combined effort of structural and biochemical studies, details of the peptidyl transfer reaction have become increasingly clearer. However, significantly less is known about the molecular events that lead to peptidyl-tRNA hydrolysis at the termination phase of translation. Here we have applied a recently introduced experimental system, which allows the ribosomal peptidyl transferase center (PTC) to be chemically engineered by the introduction of non-natural nucleoside analogs. By this approach single functional group modifications are incorporated, thus allowing their functional contributions in the PTC to be unravelled with improved precision. We show that an intact ribose sugar at the 23S rRNA residue A2602 is crucial for efficient peptidyl-tRNA hydrolysis, while having no apparent functional relevance for transpeptidation. Despite the fact that all investigated active site residues are universally conserved, the removal of the complete nucleobase or the ribose 2′-hydroxyl at A2602, U2585, U2506, A2451 or C2063 has no or only marginal inhibitory effects on the overall rate of peptidyl-tRNA hydrolysis. These findings underscore the exceptional functional importance of the ribose moiety at A2602 for triggering peptide release

Chemical engineering of the peptidyl transferase center reveals an important role of the 2′-hydroxyl group of A2451

The main enzymatic reaction of the large ribosomal subunit is peptide bond formation. Ribosome crystallography showed that A2451 of 23S rRNA makes the closest approach to the attacking amino group of aminoacyl-tRNA. Mutations of A2451 had relatively small effects on transpeptidation and failed to unequivocally identify the crucial functional group(s). Here, we employed an in vitro reconstitution system for chemical engineering the peptidyl transferase center by introducing non-natural nucleosides at position A2451. This allowed us to investigate the peptidyl transfer reaction performed by a ribosome that contained a modified nucleoside at the active site. The main finding is that ribosomes carrying a 2′-deoxyribose at A2451 showed a compromised peptidyl transferase activity. In variance, adenine base modifications and even the removal of the entire nucleobase at A2451 had only little impact on peptide bond formation, as long as the 2′-hydroxyl was present. This implicates a functional or structural role of the 2′-hydroxyl group at A2451 for transpeptidation

Venetoclax-based therapies in pediatric advanced MDS and relapsed/refractory AML: a multicenter retrospective analysis

not availabl

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

An intact ribose moiety at A2602 of 23S rRNA is

key to trigger peptidyl-tRNA hydrolysis during translation terminatio

Body-Mass-Index Associated Differences in Ortho- and Retronasal Olfactory Function and the Individual Significance of Olfaction in Health and Disease

Odor (including flavor) perception plays a major role in dietary behavior. Orthonasal olfactory function (OOF) has been shown to decrease in obese subjects. Changes in retronasal olfactory function (ROF) after weight loss and in the individual significance of olfaction (ISO) in obesity are yet to be investigated. Firstly, 15 obese subjects were recruited in a pilot study and supported to conventionally lose weight. OOF (Sniffin’ Sticks) was measured at the beginning and after 5.6 ± 1.3 months. Eleven subjects re-visited but barely lost weight and no major changes in OOF were observed. Secondly, the body-mass-index (BMI), OOF, and ROF (Candy Smell Test, CST) were recorded in subjectively olfactory-healthy subjects (SOHSs) and additionally the ISO questionnaire was collected in patients with olfactory dysfunction (OD). BMI correlated significantly negatively with odor discrimination (p = 0.00004) in 74 SOHSs and negatively with CST (p 0.05). ISO scores were significantly higher in 52 OD patients in comparison to SOHSs (p = 0.0382). Not only OOF but also ROF may decline with higher BMI. ISO does not seem to alter with BMI, but olfaction becomes more important once it is consciously impaired

Peptidyl transferase activities of gapped-cp-reconstituted subunits containing 2′-deoxyribose modifications at A2451 using CC-puromycin as acceptor substrate

<p><b>Copyright information:</b></p><p>Taken from "Chemical engineering of the peptidyl transferase center reveals an important role of the 2′-hydroxyl group of A2451"</p><p>Nucleic Acids Research 2005;33(5):1618-1627.</p><p>Published online 14 Mar 2005</p><p>PMCID:PMC1065261.</p><p>© The Author 2005. Published by Oxford University Press. All rights reserved</p> () The reaction between -acetyl-Phe-tRNA and [P]CC-puromycin was carried out for 120 min, a time point that corresponded to the endpoint of the reaction catalyzed by reconstituted wild-type large subunits. The product -acetyl-Phe-CC-puromycin (CC-Pmn-AcPhe) was resolved from CC-puromycin (CC-Pmn) by gel electrophoresis (). The control reaction (ctrl) contained the whole reaction mixture except ribosomal particles. The relative yields of product formation by gapped-cp-reconstituted subunits containing adenosine (wt), 2′-deoxyadenosine (dA), or the deoxy-abasic analog (d-aba) at 2451 are shown below the gel. () The initial rates of peptide bond formation catalyzed by the wt or the deoxy-A2451-modified large ribosomal subunit were determined from experimental points within the first 45 min of incubation. During this incubation time, no product formation with ribosomal particles carrying the deoxy-abasic site analog at position 2451 could be measured (n.d.). The rates were normalized to the rate of reconstituted subunits containing the synthetic wild-type RNA fragment (wt)

Functional classification of RUNX1 variants in familial platelet disorder with associated myeloid malignancies

SCOPUS: ar.jinfo:eu-repo/semantics/publishe