Meier–Gorlin syndrome and Wolf–Hirschhorn syndrome: two developmental disorders highlighting the importance of efficient DNA replication for normal development and neurogenesis

Microcephaly represents one of the most obvious clinical manifestations of impaired neurogenesis. Defects in the DNA damage response, in DNA repair, and structural abnormalities in centrosomes, centrioles and the spindle microtubule network have all been demonstrated to cause microcephaly in humans. Work describing novel functional defects in cell lines from individuals with either Meier–Gorlin syndrome or Wolf–Hirschhorn syndrome highlight the significance of optimal DNA replication and S phase progression for normal human development, including neurogenesis. These findings illustrate how different primary defects in processes impacting upon DNA replication potentially influence similar phenotypic outcomes, including growth retardation and microcephaly. Herein, we will describe the nature of the S phase defects uncovered for each of these conditions and highlight some of the overlapping cellular features

Whole-organism concentration ratios in wildlife inhabiting Australian uranium mining environments

Wildlife concentration ratios for 226Ra, 210Pb, 210Po and isotopes of Th and U from soil, water, and sediments were evaluated for a range of Australian uranium mining environments. Whole-organism concentration ratios (CRwo-media) were developed for 271 radionuclide-organism pairs within the terrestrial and freshwater wildlife groups. Australian wildlife often has distinct physiological attributes, such as the lower metabolic rates of macropod marsupials as compared with placental mammals. In addition, the Australian CRswo-media originate from tropical and semi-arid climates, rather than from the temperate-dominated climates of Europe and North America from which most (>90%) of internationally available CRwo-media values originate. When compared, the Australian and non-Australian CRs are significantly different for some wildlife categories (e.g. grasses, mammals) but not others (e.g. shrubs). Where differences exist, the Australian values were higher, suggesting that site-, or region-specific CRswo-media should be used in detailed Australian assessments. However, in screening studies, use of the international mean values in the Wildlife Transfer Database (WTD) appears to be appropriate, as long as the values used encompass the Australian 95th percentile values. Gaps in the Australian datasets include a lack of marine parameters, and no CR data are available for freshwater phytoplankton, zooplankton, insects, insect larvae or amphibians; for terrestrial environments, there are no data for amphibians, annelids, ferns, fungi or lichens & bryophytes. The new Australian specific parameters will aide in evaluating remediation plans and ongoing operations at mining and waste sites within Australia. They have also substantially bolstered the body of U- and Th-series CRwo-media data for use internationally

Value of black blood T2* cardiovascular magnetic resonance

Purpose To assess whether black blood T2* cardiovascular magnetic resonance is superior to conventional white blood imaging of cardiac iron in patients with thalassaemia major (TM). Materials and methods We performed both conventional white blood and black blood T2* CMR sequences in 100 TM patients to determine intra and inter-observer variability and presence of artefacts. In 23 patients, 2 separate studies of both techniques were performed to assess interstudy reproducibility. Results Cardiac T2* values ranged from 4.5 to 43.8 ms. The mean T2* values were not different between black blood and white blood acquisitions (20.5 vs 21.6 ms, p = 0.26). Compared with the conventional white blood diastolic acquisition, the coefficient of variance of the black blood CMR technique was superior for intra-observer reproducibility (1.47% vs 4.23%, p < 0.001), inter-observer reproducibility (2.54% vs 4.50%, p < 0.001) and inter-study reproducibility (4.07% vs 8.42%, p = 0.001). Assessment of artefacts showed a superior score for black blood vs white blood scans (4.57 vs 4.25; p < 0.001). Conclusions Black blood T2* CMR has superior reproducibility and reduced imaging artefacts for the assessment of cardiac iron, in comparison with the conventional white blood technique, which make it the preferred technique for clinical practice

Oral-Facial-Digital syndrome Type I cells exhibit impaired DNA repair; unanticipated consequences of defective OFD1 outside of the cilia network

Defects in OFD1 underlie the clinically complex ciliopathy, Oral-Facial-Digital syndrome Type I (OFD Type I). Our understanding of the molecular, cellular and clinical consequences of impaired OFD1 originate from its characterised roles at the centrosome/basal body/cilia network. Nonetheless, the first described OFD1 interactors were components of the TIP60 histone acetyltransferase complex. We find that OFD1 can also localise to chromatin and its reduced expression is associated with mislocalization of TIP60 in patient-derived cell lines. TIP60 plays important roles in controlling DNA repair. OFD Type I cells exhibit reduced histone acetylation and altered chromatin dynamics in response to DNA double strand breaks (DSBs). Furthermore, reduced OFD1 impaired DSB repair via homologous recombination repair (HRR). OFD1 loss also adversely impacted upon the DSB-induced G2-M checkpoint, inducing a hypersensitive and prolonged arrest. Our findings show that OFD Type I patient cells have pronounced defects in the DSB-induced histone modification, chromatin remodelling and DSB-repair via HRR; effectively phenocopying loss of TIP60. These data extend our knowledge of the molecular and cellular consequences of impaired OFD1, demonstrating that loss of OFD1 can negatively impact upon important nuclear events; chromatin plasticity and DNA repair

Right ventricular volumes and function in thalassemia major patients in the absence of myocardial iron overload

<p>Abstract</p> <p>Aim</p> <p>We aimed to define reference ranges for right ventricular (RV) volumes, ejection fraction (EF) in thalassemia major patients (TM) without myocardial iron overload.</p> <p>Methods and results</p> <p>RV volumes, EF and mass were measured in 80 TM patients who had no myocardial iron overload (myocardial T2* > 20 ms by cardiovascular magnetic resonance). All patients were receiving deferoxamine chelation and none had evidence of pulmonary hypertension or other cardiovascular comorbidity. Forty age and sex matched healthy non-anemic volunteers acted as controls. The mean RV EF was higher in TM patients than controls (males 66.2 ± 4.1% vs 61.6 ± 6%, p = 0.0009; females 66.3 ± 5.1% vs 62.6 ± 6.4%, p = 0.017), which yielded a raised lower threshold of normality for RV EF in TM patients (males 58.0% vs 50.0% and females 56.4% vs 50.1%). RV end-diastolic volume index was higher in male TM patients (mean 98.1 ± 17.3 mL vs 88.4 ± 11.2 mL/m2, p = 0.027), with a higher upper limit (132 vs 110 mL/m2) but this difference was of borderline significance for females (mean 86.5 ± 13.6 mL vs 80.3 ± 12.8 mL/m2, p = 0.09, with upper limit of 113 vs 105 mL/m2). The cardiac index was raised in TM patients (males 4.8 ± 1.0 L/min vs 3.4 ± 0.7 L/min, p < 0.0001; females 4.5 ± 0.8 L/min vs 3.2 ± 0.8 L/min, p < 0.0001). No differences in RV mass index were identified.</p> <p>Conclusion</p> <p>The normal ranges for functional RV parameters in TM patients with no evidence of myocardial iron overload differ from healthy non-anemic controls. The new reference RV ranges are important for determining the functional effects of myocardial iron overload in TM patients.</p

Effect of deferiprone or deferoxamine on right ventricular function in thalassemia major patients with myocardial iron overload

<p>Abstract</p> <p>Background</p> <p>Thalassaemia major (TM) patients need regular blood transfusions that lead to accumulation of iron and death from heart failure. Deferiprone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular (LV) function but little is known of their relative effects on the right ventricle (RV), which is being increasingly recognised as an important prognostic factor in cardiomyopathy. Therefore data from a prospective randomised controlled trial (RCT) comparing these chelators was retrospectively analysed to assess the RV responses to these drugs.</p> <p>Methods</p> <p>In the RCT, 61 TM patients were randomised to receive either deferiprone or deferoxamine monotherapy, and CMR scans for T2* and cardiac function were obtained. Data were re-analysed for RV volumes and function at baseline, and after 6 and 12 months of treatment.</p> <p>Results</p> <p>From baseline to 12 months, deferiprone reduced RV end systolic volume (ESV) from 37.7 to 34.2 mL (p = 0.008), whilst RV ejection fraction (EF) increased from 69.6 to 72.2% (p = 0.001). This was associated with a 27% increase in T2* (p < 0.001) and 3.1% increase in LVEF (p < 0.001). By contrast, deferoxamine showed no change in RVESV (38.1 to 39.1 mL, p = 0.38), or RVEF (70.0 to 69.9%, p = 0.93) whereas the T2* increased by 13% (p < 0.001), but with no change in LVEF (0.32%; p = 0.66). Analysis of between drugs treatment effects, showed significant improvements favouring deferiprone with a mean effect on RVESV of -1.82 mL (p = 0.014) and 1.16% for RVEF (p = 0.009). Using regression analysis the improvement in RVEF at 12 months was shown to be greater in patients with lower baseline EF values (p < 0.001), with a significant difference in RVEF of 3.5% favouring deferiprone over deferoxamine (p = 0.012).</p> <p>Conclusion</p> <p>In this retrospective analysis of a prospective RCT, deferiprone monotherapy was superior to deferoxamine for improvement in RVEF and end-systolic volume. This improvement in the RV volumes and function may contribute to the improved cardiac outcomes seen with deferiprone.</p

Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome

A novel microduplication syndrome involving various-sized contiguous duplications in 17p13.3 has recently been described, suggesting that increased copy number of genes in 17p13.3, particularly PAFAH1B1, is associated with clinical features including facial dysmorphism, developmental delay, and autism spectrum disorder. We have previously shown that patient-derived cell lines from individuals with haploinsufficiency of RPA1, a gene within 17p13.3, exhibit an impaired ATR-dependent DNA damage response (DDR). Here, we show that cell lines from patients with duplications specifically incorporating RPA1 exhibit a different although characteristic spectrum of DDR defects including abnormal S phase distribution, attenuated DNA double strand break (DSB)-induced RAD51 chromatin retention, elevated genomic instability, and increased sensitivity to DNA damaging agents. Using controlled conditional over-expression of RPA1 in a human model cell system, we also see attenuated DSB-induced RAD51 chromatin retention. Furthermore, we find that transient over-expression of RPA1 can impact on homologous recombination (HR) pathways following DSB formation, favouring engagement in aberrant forms of recombination and repair. Our data identifies unanticipated defects in the DDR associated with duplications in 17p13.3 in humans involving modest RPA1 over-expression