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Catalytic inhibition of topoisomerase II during G2 phase delays onset of mitosis due to the activation of the so‐called decatenation checkpoint. This checkpoint is less known compared with the extensively studied G2 DNA damage checkpoint and is partially compromised in many tumor cells. We recently identified MCPH1 as a key regulator that confers cells with the capacity to adapt to the decatenation checkpoint. In the present work, we have explored the contributions of checkpoint kinase 1 (Chk1) and polo‐like kinase 1 (Plk1), in order to better understand the molecular basis of decatenation checkpoint. Our results demonstrate that Chk1 function is required to sustain the G2 arrest induced by catalytic inhibition of Topo II. Interestingly, Chk1 loss of function restores adaptation in cells lacking MCPH1. Furthermore, we demonstrate that Plk1 function is required to bypass the decatenation checkpoint arrest in cells following Chk1 inhibition. Taken together, our data suggest that MCPH1 is critical to allow checkpoint adaptation by counteracting Chk1‐mediated inactivation of Plk1. Importantly, we also provide evidence that MCPH1 function is not required to allow recovery from this checkpoint, which lends support to the notion that checkpoint adaptation and recovery are different mechanisms distinguished in part by specific effectors. [ABSTRACT FROM AUTHOR]

Introduction: IFN lambda (type III‐IFN‐λ1) is a molecule primarily produced by epithelial cells that provides an important first‐line defence against viral respiratory infections and has been linked to the pathogenesis of viral‐induced wheezing in early life. The goal of this study was to better understand the regulation of innate IFN‐lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections. Methods: IFN‐lambda protein levels were quantified: (a) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n = 8 donors); and (b) in nasal aspirates of young children (≤3 years) hospitalized with viral respiratory infection (n = 138) and in uninfected controls (n = 74). In vivo IFN‐lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters. Results: Our in vitro experiments showed that the poly(I:C)‐induced innate production of IFN lambda in human infant AECs is regulated by (a) p38‐MAPK/NF‐kB dependent mechanism; and (b) exposure to pro‐inflammatory signals such as IL1β. Our in vivo studies demonstrated that (a) infants (<18 months) had higher virus‐induced IFN‐lambda airway secretion; (b) subjects with RSV infection showed the highest IFN‐lambda airway levels; and (c) individuals with the highest virus‐induced IFN‐lambda levels (>90th percentile) had higher viral loads and were more likely to have respiratory sick visits within 12 months of discharge (OR = 5.8). Conclusion: IFN‐lambda responses to dsRNA in the human infant airway epithelium are regulated by p38‐MAPK and NF‐kB signalling. High in vivo IFN‐lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children. [ABSTRACT FROM AUTHOR]

The 22q11.2 deletion syndrome is typically caused by haploinsufficiency of a 3 Mb region that extends from LCR22-A until LCR22-D, while the recurrent recombination between any of the LCR22-D to H causes the 22q11.2 distal deletion syndrome. Here, we describe three patients with a de novo atypical ∼1.4 Mb 22q11.2 deletion that involves LCR22-C to a region beyond D (LCR22-C to D/E), encompassing the distal portion of the typical deleted region and the proximal portion of the distal deletion. We also review six previous published patients with the same rearrangement and compare their features with those found in patients with overlapping deletions. Patients with LCR22-C to D/E deletion present a recognizable phenotype characterized by facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay. Genotype-phenotype analysis of the patients indicates that CRKL and MAPK1 genes play an important role as causative factors for the main clinical features of the syndrome. In particular, CRKL gene seems to be involved in the occurrence of conotruncal cardiac anomalies, mainly tetralogy of Fallot. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The transcription factor EGR2 is expressed in Schwann cells, where it controls peripheral nerve myelination. Mutations of EGR2 have been found in patients with congenital hypomyelinating neuropathy or Charcot-Marie-Tooth disease type 1D. In a patient with congenital amyelinating neuropathy, we observed pathological abnormalities recapitulating the peripheral nervous system phenotype of homozygous Egr2-null mice. This patient, born from consanguineous parents, showed no EGR2 immunoreactivity in Schwann cells and harbored a homozygous 10.7-kilobase-long deletion encompassing a myelin-specific enhancer of EGR2. This regulatory mutation is the first genetic abnormality associated with congenital amyelinating neuropathy in humans. ANN NEUROL 2012; [ABSTRACT FROM AUTHOR]

Background: Rubinstein‐Taybi syndrome (RSTS) is a rare congenital disorder characterized by broad thumbs and halluces, intellectual disability, distinctive facial features, and growth retardation. Clinical manifestations of RSTS are varied and overlap with other syndromes' phenotype, which makes clinical diagnosis challenging. CREBBP is the major causative gene (55%–60% of the cases), whereas pathogenic variants found in EP300 represent the molecular cause in 8% of RSTS patients. A wide range of CREBBP pathogenic variants have been reported so far, including point mutations (30%–50%) and large deletions (10%). Methods: The aim of this study was to characterize the CREBBP genetic variant spectrum in 39 RSTS patients using Multiplex Ligation‐dependent Probe Amplification and DNA sequencing techniques (Sanger and Trio‐based whole‐exome sequencing). Results: We identified 15 intragenic deletions/duplications, ranging from one exon to the entire gene. As a whole, 25 de novo point variants were detected: 4 missense, 12 nonsense, 5 frameshift, and 4 splicing pathogenic variants. Three of them were classified as of uncertain significance and one of the patients carried two different variants. Conclusion: Seventeen of the 40 genetic variants detected were reported for the first time in this work contributing, thus, to expand the molecular knowledge of this complex disorder. [ABSTRACT FROM AUTHOR]

Background: Management of Helicobacter pylori infection has been expanded from the gastroenterology specialist (GS) to primary care physicians (PCPs), with a large increase in requests for urea breath tests (UBT). Due to the lack of evidence at this level, we evaluated the appropriateness of UBT indications and treatment for H pylori infections between PCPs and GSs and the effect of introducing specific counseling to PCPs. Materials and Methods: This was a quasi‐experimental study. Phase I included 650 consecutive UBT requested by PCPs (400) and GSs (250). Indications and treatments were classified as appropriate or inappropriate based on national guidelines. Data on eradication rates were also collected. In phase II, 240 UBT and patients' treatment outcomes were analyzed after individually counseling PCPs on both aspects. Results: Of 1049 UBT, inappropriate indications in phase I were significantly higher in tests requested by PCP compared with GS (35.9% vs 7.2%; P < 0.001). Inappropriate treatment regimens were significantly higher for PCPs in phase I (65.8% vs 26.4%; P < 0.001). Consequently, eradication rates were significantly lower in patients treated by PCPs compared with those treated by GS (63.7% vs 81.4%; P = 0.004). A significant increase in adherence to appropriate treatment regimens (75.8% vs 34.2%; P < 0.001) and eradication rates (79.2% vs 63.7%; P = 0.002) were observed in the PCP group after counseling; however, the appropriateness of indications did not improve. Conclusions: Patients infected with H pylori managed at the primary care level had poorer outcomes. The introduction of specific counseling for PCPs significantly improved treatment management, but not indications. [ABSTRACT FROM AUTHOR]

Microdeletions of the 2q31.1 region are rare. We present the clinical and molecular findings of eight previously unreported patients with overlapping deletions in 2q31.1. The patients have a variable clinical phenotype and present with developmental delay (7/8), growth retardation (5/8), seizures (2/8) and a craniofacial dysmorphism consisting of microcephaly (4/8), short palpebral fissures (7/8), broad eyebrows with lateral flare (7/8), low-set ears with thickened helices and lobules (5/8), and micrognathia (6/8). Additional congenital anomalies were noted, including limb abnormalities (8/8), heart defects (3/8), genital anomalies (3/8), and craniosynostosis (1/8). Six of these microdeletions, ranging in size from 1.24 to 8.35 Mb, were identified by array CGH, one larger deletion (19.7 Mb) was detected by conventional karyotyping and further characterized by array CGH analysis. The smallest region of overlap in all eight patients spans at most 88 kb and includes only the WIPF1 gene. This gene codes for the WAS/WASL interacting protein family member 1. The patients described here do not present with clinical signs of the Wiskott-Aldrich syndrome and the deletion of this single gene does not allow explaining the phenotype in our patients. It is likely that the deletion of different but overlapping sets of genes from 2q31 is responsible for the clinical variability in these patients. To further dissect the complex phenotype associated with deletions in 2q31, additional patients with overlapping phenotypes should be examined with array CGH. This should help to link particular phenotypes to specific genes, and add to our understanding of the underlying developmental processes., (Copyright 2010 Wiley-Liss, Inc.)