Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles

PURPOSE. To investigate the role of two deep-intronic ABCA4 variants, that showed a mild splice defect in vitro and can occur on the same allele as the low penetrant c.5603A>T, in Stargardt disease (STGD1). METHODS. Ophthalmic data were assessed of 18 STGD1 patients who harbored c.769-784C>T or c.4253+43G>A in combination with a severe ABCA4 variant. Subjects carrying c.[769784C>T; 5603A>T] were clinically compared with a STGD1 cohort previously published carrying c.5603A>T noncomplex. We calculated the penetrances of the intronic variants using ABCA4 allele frequency data of the general population and investigated the effect of c.769-784C>T on splicing in photoreceptor progenitor cells (PPCs). RESULTS. Mostly, late-onset, foveal-sparing STGD1 was observed among subjects harboring c.769-784C>T or c.4253+43G>A (median age of onset, 54.5 and 52.0 years, respectively). However, ages of onset, phenotypes in fundo, and visual acuity courses varied widely. No significant clinical differences were observed between the c.[769-784C>T; 5603A>T] cohort and the c.4253+43G>A or the c.5603A>T cohort. The penetrances of c.769-784C>T (20.5%-39.6%) and c.4253+43G>A (35.8%-43.1%) were reduced, when not considering the effect of yet unidentified or known factors in cis, such as c.5603A>T (identified in 7/7 probands with c.769-784C>T; 1/8 probands with c.4253+43G>A). Variant c.769-784C>T resulted in a pseudo-exon insertion in 15% of the total mRNA (i.e., similar to 30% of the c.769-784C>T allele alone). CONCLUSIONS. Two mild intronic ABCA4 variants could further explain missing heritability in late-onset STGD1, distinguishing it from AMD. The observed clinical variability and calculated reduced penetrance urge research into modifiers within and outside of the ABCA4 gene

The common ABCA4 variant p.Asn1868ile shows nonpenetrance and variable expression of stargardt disease when present in trans with severe variants

PURPOSE. To assess the occurrence and the disease expression of the common p.Asn1868Ile variant in patients with Stargardt disease (STGD1) harboring known, monoallelic causal ABCA4 variants. METHODS. The coding and noncoding regions of ABCA4 were sequenced in 67 and 63 STGD1 probands respectively, harboring monoallelic ABCA4 variants. In case p.Asn1868Ile was detected, segregation analysis was performed whenever possible. Probands and affected siblings harboring p.Asn1868Ile without additional variants in cis were clinically evaluated retrospe

Ovalbumin-containing core-shell implants suitable to obtain a delayed IgG1 antibody response in support of a biphasic pulsatile release profile in mice

A single-injection vaccine formulation that provides for both a prime and a boost immunization would have various advantages over a multiple-injection regime. For such a vaccine formulation, it is essential that the booster dose is released after a certain, preferably adjustable, lag time. In this study we investigated whether a core-shell based implant, containing ovalbumin as core material and poly(DL-lactic-co-glycolic acid) of various monomer ratios as shell material can be used to obtain such a booster release. An in vitro release study showed that the lag time after which the ovalbumin was released from the core-shell implant increased with increasing lactic to glycolic acid ratio of the polymer and ranged from 3-6 weeks. Fluorescence spectroscopy showed minimal differences between native ovalbumin and ovalbumin from core-shell implants that were incubated until just before the observed in vitro release. In addition, mice immunized with a subcutaneous inserted core-shell implant containing ovalbumin showed an ovalbumin-specific IgG1 antibody response after a lag time of 4 or 6-8 weeks. Moreover, delayed release of ovalbumin caused higher IgG1 antibody titers than conventional subcutaneous vaccination with ovalbumin dissolved in PBS. Collectively, these findings could contribute to the further development of a single-injection vaccine, making multiple injections of the vaccine superfluous

The Virtual Sociality of Rights: The Case of Women\u27s Rights are Human Rights

This essay traces the relationship between activists and academics involved in the campaign for women\u27s rights as human rights as a case study of the relationship between different classes of what I call knowledge professionals self-consciously acting in a transnational domain. The puzzle that animates this essay is the following: how was it that at the very moment at which a critique of rights and a reimagination of rights as rights talk proved to be such fertile ground for academic scholarship did the same rights prove to be an equally fertile ground for activist networking and lobbying activities? The paper answers this question with respect to the work of self-reflexivity in creating a virtual sociality of rights

Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa

Background: Recent findings suggesting that Abelson helper integration site 1 (AHI1) is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether AHI1 variants cause non-syndromic retinitis pigmentosa (RP). Methods: Exome sequencing was performed in three probands with RP. The effects of the identified missense variants in AHI1 were predicted by three-dimensional structure homology modelling. Ciliary parameters were evaluated in patient's fibroblasts, and recombinant mutant proteins were expressed in ciliated retinal pigmented epithelium cells. Results: In the three patients with RP, three sets of compound heterozygous variants were detected in AHI1 (c.2174G>A; p.Trp725* and c.2258A>T; p.Asp753Val, c.660delC; p.Ser221Glnfs*10 and c.2090C>T; p.Pro697Leu, c.2087A>G; p.His696Arg and c.2429C>T; p.Pro810Leu). All four missense variants were present in the conserved WD40 domain of Jouberin, the ciliary protein encoded by AHI1, with variable predicted implications for the domain structure. No significant changes in the percentage of ciliated cells, nor in cilium length or intraflagellar transport were detected. However, expression of mutant recombinant Jouberin in ciliated cells showed a significantly decreased enrichment at the ciliary base. Conclusions: This report confirms that mutations in AHI1 can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated AHI1 variants on protein function, thus proposing a new genotype-phenotype correlation for AHI1 mutation associated retinal ciliopathies

Effects of baroreceptor activation therapy on dipping behavior in patients with refractory hypertension - A prospective study of nondipper patients

Non-dipping is defined as an inadequate night-time blood pressure reduction of less than < 10 %. This inadequate reduction as well as an increase in nocturnal blood pressure is associated with an increased cardiovascular risk. The baroreflex activation therapy (BAT) is an interventional, sympathicoinhibitory proce-dure that allows the programming of different time intervals in order to achieve a differen-tiated influence on daily blood pressure. The primary objective of the present study was to analyze if escalating of nighttime BAT programming over a period of three months might contribute to an improvement of dip-ping status. In addition, parameters of pulse wave velocity, changes in practice und outpa-tient 24-hour- blood pressure as well as the side effect profile of the therapy were record-ed. In the group of 23 included patients (mean age 66 ± 9 years, mean BMI 32 ± 6kg/m2, 12 (50 %) diabetes mellitus, 16 (67 %) hyperlipoproteinemia, 12 (50 %) chronic kidney disease, 3 (13 %) on renal replacement therapy) an improvement of the systolic dipping from 2 6 % to 68 % (p = 0.03) as well as an improvement of the dipping profile could be shown after three months of BAT nocturnal dose escalation. With regard to night pro-gramming settings, an increase in pulse width from 237 ± 161µs to 267 ± 170µs (p = <  0.03) could be achieved, while amplitude (p = 0.95) and frequency (p = 0.09) re-mained unchanged.  Ambulatory 24-hour-blood pressure values remained unchanged after three months BAT escalation, as did the practice blood pressure, pulse wave velocity and the number of anti-hypertensive drugs. These data suggest that a differentiated programming of BAT may lead to an improvement in nocturnal dipping in patients with resistant hypertension, which may lead to beneficial cardiovascular effects beyond the overall blood pressure reduction.  The present data could help to generate optimized programming protocols for the BAT to achieve a standardized programming procedure, an optimal effectiveness on the BP and especially on the dipping profile of the patients with resistant hypertension. Larger ran-domized, controlled trials are needed to investigate the effect of BAT on dipping and car-diovascular risk.2022-02-1