Population specificity of the DNAI1 gene mutation spectrum in primary ciliary dyskinesia (PCD)

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>DNAI1 </it>gene, encoding a component of outer dynein arms of the ciliary apparatus, are the second most important genetic cause of primary ciliary dyskinesia (PCD), the genetically heterogeneous recessive disorder with the prevalence of ~1/20,000. The estimates of the <it>DNAI1 </it>involvement in PCD pathogenesis differ among the reported studies, ranging from 4% to 10%.</p> <p>Methods</p> <p>The coding sequence of <it>DNAI1 </it>was screened (SSCP analysis and direct sequencing) in a group of PCD patients (157 families, 185 affected individuals), the first ever studied large cohort of PCD patients of Slavic origin (mostly Polish); multiplex ligation-dependent probe amplification (MLPA) analysis was performed in a subset of ~80 families.</p> <p>Results</p> <p>Three previously reported mutations (IVS1+2-3insT, L513P and A538T) and two novel missense substitutions (C388Y and G515S) were identified in 12 families (i.e. ~8% of non-related Polish PCD patients). The structure of background SNP haplotypes indicated common origin of each of the two most frequent mutations, IVS1+2-3insT and A538T. MLPA analysis did not reveal any significant differences between patients and control samples. The Polish cohort was compared with all the previously studied PCD groups (a total of 487 families): IVS1+2-3insT remained the most prevalent pathogenetic change in <it>DNAI1 </it>(54% of the mutations identified worldwide), and the increased global prevalence of A538T (14%) was due to the contribution of the Polish cohort.</p> <p>Conclusions</p> <p>The worldwide involvement of <it>DNAI1 </it>mutations in PCD pathogenesis in families not preselected for ODA defects ranges from 7 to 10%; this global estimate as well as the mutation profile differs in specific populations. Analysis of the background SNP haplotypes suggests that the increased frequency of chromosomes carrying A538T mutations in Polish patients may reflects local (Polish or Slavic) founder effect. Results of the MLPA analysis indicate that no large exonic deletions are involved in PCD pathogenesis.</p

Housing Benefit reform and the private rented sector in the UK : on the deleterious effects of short-term, ideological "knowledge"

This paper draws on the figurational sociology of Norbert Elias in understanding the current housing crisis in the UK: one which emphasizes the social interdependencies between individuals and groups, and the power relations that characterise them, in explaining household behaviour. It is argued that such an approach can contribute to a better understanding of housing processes and their differentiated outcomes. At the same time, this analysis exposes the myriad negative consequences that emerge from short-term housing policies based on static, over-simplified assumptions and applied to an ever-increasingly complex housing figuration, which is constantly in flux. These arguments are made with reference to empirical evidence on the impact of changes to Housing Benefit in the private rented sector, which shows how neoliberal housing policy contributes to long-term detrimental effects on marginalised households and groups. Through this example, it is argued that the governmental presentation of welfare reforms differs markedly from the reality of consequences on the ground and corresponds to 'neoliberal state-crafting'. It is suggested that any approach to understanding the complexities of the housing system must retain a focus on historical change, precedents and fluctuations in power balances to avoid the pernicious "retreat into the present" characteristic of policy

Mutations in Radial Spoke Head Genes and Ultrastructural Cilia Defects in East-European Cohort of Primary Ciliary Dyskinesia Patients

Primary ciliary dyskinesia (PCD) is a rare (1/20,000), multisystem disease with a complex phenotype caused by the impaired motility of cilia/flagella, usually related to ultrastructural defects of these organelles. Mutations in genes encoding radial spoke head (RSPH) proteins, elements of the ciliary ultrastructure, have been recently described. However, the relative involvement of RSPH genes in PCD pathogenesis remained unknown, due to a small number of PCD families examined for mutations in these genes. The purpose of this study was to estimate the involvement of RSPH4A and RSPH9 in PCD pathogenesis among East Europeans (West Slavs), and to shed more light on ultrastructural ciliary defects caused by mutations in these genes. The coding sequences of RSPH4A and RSPH9 were screened in PCD patients from 184 families, using single strand conformational polymorphism analysis and sequencing. Two previously described (Q109X; R490X) and two new RSPH4A mutations (W356X; IVS3_2–5del), in/around exons 1 and 3, were identified; no mutations were found in RSPH9. We estimate that mutations in RSPH4A, but not in RSPH9, are responsible for 2–3% of cases in the East European PCD population (4% in PCD families without situs inversus; 11% in families preselected for microtubular defects). Analysis of the SNP-haplotype background provided insight into the ancestry of repetitively found mutations (Q109X; R490X; IVS3_2–5del), but further studies involving other PCD cohorts are required to elucidate whether these mutations are specific for Slavic people or spread among other European populations. Ultrastructural defects associated with the mutations were analyzed in the transmission electron microscope images; almost half of the ciliary cross-sections examined in patients with RSPH4A mutations had the microtubule transposition phenotype (9+0 and 8+1 pattern). While microtubule transposition was a prevalent ultrastructural defect in cilia from patients with RSPH4A mutations, similar defects were also observed in PCD patients with mutations in other genes

Temporal Integration of Movement: The Time-Course of Motion Streaks Revealed by Masking

Temporal integration in the visual system causes fast-moving objects to leave oriented ‘motion streaks’ in their wake, which could be used to facilitate motion direction perception. Temporal integration is thought to occur over 100 ms in early cortex, although this has never been tested for motion streaks. Here we compare the ability of fast-moving (‘streaky’) and slow-moving fields of dots to mask briefly flashed gratings either parallel or orthogonal to the motion trajectory. Gratings were presented at various asynchronies relative to motion onset (from to ms) to sample the time-course of the accumulating streaks. Predictions were that masking would be strongest for the fast parallel condition, and would be weak at early asynchronies and strengthen over time as integration rendered the translating dots more streaky and grating-like. The asynchrony where the masking function reached a plateau would correspond to the temporal integration period. As expected, fast-moving dots caused greater masking of parallel gratings than orthogonal gratings, and slow motion produced only modest masking of either grating orientation. Masking strength in the fast, parallel condition increased with time and reached a plateau after 77 ms, providing an estimate of the temporal integration period for mechanisms encoding motion streaks. Interestingly, the greater masking by fast motion of parallel compared with orthogonal gratings first reached significance at 48 ms before motion onset, indicating an effect of backward masking by motion streaks

Citizenship Norms in Eastern Europe

Research on Eastern Europe stresses the weakness of its civil society and the lack of political and social involvement, neglecting the question: What do people themselves think it means to be a good citizen? This study looks at citizens’ definitions of good citizenship in Poland, Slovenia, the Czech Republic and Hungary, using 2002 European Social Survey data. We investigate mean levels of civic mindedness in these countries and perform regression analyses to investigate whether factors traditionally associated with civic and political participation are also correlated with citizenship norms across Eastern Europe. We show that mean levels of civic mindedness differ significantly across the four Eastern European countries. We find some support for theories on civic and political participation when explaining norms of citizenship, but also demonstrate that individual-level characteristics are differently related to citizenship norms across the countries of our study. Hence, our findings show that Eastern Europe is not a monolithic and homogeneous bloc, underscoring the importance of taking the specificities of countries into account

In vitro culturing of ciliary respiratory cells—a model for studies of genetic diseases

Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by the impaired functioning of ciliated cells. Its diagnosis is based on the analysis of the structure and functioning of cilia present in the respiratory epithelium (RE) of the patient. Abnormalities of cilia caused by hereditary mutations closely resemble and often overlap with defects induced by the environmental factors. As a result, proper diagnosis of PCD is difficult and may require repeated sampling of patients’ tissue, which is not always possible. The culturing of differentiated cells and tissues derived from the human RE seems to be the best way to diagnose PCD, to study genotype–phenotype relations of genes involved in ciliary dysfunction, as well as other aspects related to the functioning of the RE. In this review, different methods of culturing differentiated cells and tissues derived from the human RE, along with their potential and limitations, are summarized. Several considerations with respect to the factors influencing the process of in vitro differentiation (cell-to-cell interactions, medium composition, cell-support substrate) are also discussed

Mutations in ZMYND10, a Gene Essential for Proper Axonemal Assembly of Inner and Outer Dynein Arms in Humans and Flies, Cause Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a ciliopathy characterized by airway disease, infertility, and laterality defects, often caused by dual loss of the inner dynein arms (IDAs) and outer dynein arms (ODAs), which power cilia and flagella beating. Using whole-exome and candidate-gene Sanger resequencing in PCD-affected families afflicted with combined IDA and ODA defects, we found that 6/38 (16%) carried biallelic mutations in the conserved zinc-finger gene BLU (ZMYND10). ZMYND10 mutations conferred dynein-arm loss seen at the ultrastructural and immunofluorescence level and complete cilia immotility, except in hypomorphic p.Val16Gly (c.47T&gt;G) homozygote individuals, whose cilia retained a stiff and slowed beat. In mice, Zmynd10 mRNA is restricted to regions containing motile cilia. In a Drosophila model of PCD, Zmynd10 is exclusively expressed in cells with motile cilia: chordotonal sensory neurons and sperm. In these cells, P-element-mediated gene silencing caused IDA and ODA defects, proprioception deficits, and sterility due to immotile sperm. Drosophila Zmynd10 with an equivalent c.47T&gt;G (p.Val16Gly) missense change rescued mutant male sterility less than the wild-type did. Tagged Drosophila ZMYND10 is localized primarily to the cytoplasm, and human ZMYND10 interacts with LRRC6, another cytoplasmically localized protein altered in PCD. Using a fly model of PCD, we conclude that ZMYND10 is a cytoplasmic protein required for IDA and ODA assembly and that its variants cause ciliary dysmotility and PCD with laterality defects