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Genetic testing in patients with suspected hereditary kidney disease may not reveal the genetic cause for the disorder as potentially pathogenic variants can reside in genes that are not yet known to be involved in kidney disease. To help identify these genes, we have developed KidneyNetwork, that utilizes tissue-specific expression to predict kidney-specific gene functions.KidneyNetwork is a novel method that we used to enrich a kidney RNA-sequencing co-expression network of 878 samples with a multi-tissue network of 31,499 samples. It then uses expression patterns to predict which genes have a kidney-related function and which (disease) phenotypes might result from variants in these genes, based on established gene-phenotype associations. We applied KidneyNetwork to prioritize rare variants in exome sequencing data from 13 kidney disease patients without a genetic diagnosis.KidneyNetwork can accurately predict kidney-specific gene functions and (kidney disease) phenotypes for disease-associated genes. Applying it to exome sequencing data of kidney disease patients allowed us to highlight a convincing candidate gene for kidney and liver cysts: ALG6.We present KidneyNetwork, a kidney-specific co-expression network that accurately predicts which genes have kidney-specific functions and can result in kidney disease. We show the added value of KidneyNetwork by applying it to kidney disease patients without a molecular diagnosis and consequently, we propose ALG6 as candidate gene in one of these patients. We designed an easy-to-use online interface that allows clinicians and researchers to use gene expression and co-regulation data and gene-phenotype connections to accelerate advances in hereditary kidney disease diagnosis and research.

BACKGROUND AND AIMS Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. METHOD We collected phenotypic data of all participants. Genetic analysis was conducted by either exome or whole genome sequencing, respectively. We used Sanger sequencing for variant confirmation and segregation analysis and performed in-silico analysis of identified missense variants. In an ENU-induced mouse model, we examined mice with the mutation Robo1Ile270Thr/Ile270Thr. RESULTS By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses from Germany, France, Turkey, Japan and the USA with biallelic truncating or combined missense and truncating variants in ROBO1. Renal and genitourinary manifestation included unilateral or bilateral renal agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation and increased renal echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects (Figure 1). By in-silico analysis, we determined the functional significance of identified missense variants and observed absence of renal ROBO1 expression in both human and murine mutant tissues (Figure 2). CONCLUSION This study describes six live-born and two non-viable individuals with syndromic CAKUT due to probably deleterious ROBO1 variants. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. In conclusion, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Conversely, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for renal involvement is indicated.

We examine how organizations can challenge institutions that are coercively protected by powerful elites – guarded institutions – when they are unable or unwilling to advocate publicly against them. To do so, we draw on an in-depth qualitative study of efforts to combat child marriage in Indonesia. We explore how an international children’s rights organization worked alongside local NGOs and activists to disrupt the institution of child marriage through two discrete strategies: the crafting of an alter ego that takes the appearance of a social movement that has emanated from the grassroots but is actually highly organized; and the use of this alter ego to support the incubation of public dissent by means of a high-stakes event. We contribute to the literature by developing a theorized account of how organizations can challenge guarded institutions when they cannot speak out – an important organizational problem that has received limited attention. We also challenge the theoretical distinction that has been drawn between the organizational mobilization of activists, often referred to as astroturfing, and seemingly organic mobilization that is said to emerge at the grassroots.

BACKGROUND AND AIMS NEK8/NPHP9 encodes a protein that localizes to the primary cilium. Biallelic NEK8 variants are known to cause multiorgan developmental defects, including kidney cystic dysplasia and extensive extra-renal defects, with heterozygous carrier parents being asymptomatic [1]. This autosomal recessive inheritance is the most common inheritance mode for ciliopathies. Complementary to this, we now propose a dominant negative effect for specific heterozygous NEK8 missense variants in the kinase domain resulting in an autosomal-dominant ciliopathy. METHOD We performed genetic testing in patients from several medical centers. To explore the consequences of the identified NEK8 variants, we are performing cilia staining assays in patients' skin fibroblast and kidney cells, as well as in mIMCD3 cells overexpressing the identified variants. Furthermore, we are examining the impact of the NEK8 variants on replication stress response. RESULTS We identified three distinct heterozygous NEK8 variants in 12 families (Table 1), all leading to missense alterations in the kinase domain. Interestingly the p.Arg45Trp variant is a recurrent variant we detected in 10 unrelated families. All patients have a kidney phenotype that varies from mild focal segmental glomerulosclerosis to prenatal presentation with polycystic kidneys. Most patients have kidney failure needing kidney replacement therapy at varying ages of onset. In all patients, we thoroughly checked whether a second variant could be found. Furthermore, the large symptomatic family and de novo occurrences favor a dominant inheritance mode. Our preliminary results from functional studies show abnormal primary cilia formation in serum-starved cells as well as increased replication stress. CONCLUSION We present the first evidence for a pathogenic effect of heterozygous NEK8 variants. Remarkably our patients present with a kidney limited phenotype as compared to the multiorgan defects found in patients with biallelic variants. This reveals a new mode of inheritance for NEK8 variants and expands genotype-phenotype correlations for this gene.

Why do ideas that have been successfully moved across highly different contexts subsequently fail? To answer this question, we use longitudinal data on the Dutch organization Villages for Africa that introduced ‘macro-credit’ loans to rural Tanzanians that would enable them to establish their own village enterprises. Only two years after the seemingly successful implementation of the idea, it collapsed. Our findings allow us to make two key contributions. First, we provide a process model of high-distance translation that shows how proponents can strategically introduce an idea across highly different contexts by ‘culturally detaching’ it from its institutional origins, leading to the idea being ‘culturally assimilated’ into the recipient context. But, although cultural detachment and cultural assimilation indicate the successful translation of an idea, the means of doing so can later prompt its rejection. We call this the reactance effect of translations across highly different contexts. Second, we showcase the role of history for translation theory more generally. History – particularly the historical relationship between the socio-cultural categories of the mzungu (Swahili: “foreigner”) and the villagers –influenced the way in which the macro-credit idea could be introduced to villagers and played a key role in its subsequent rejection.

We explore the lived experience of organizational scholars who have conducted fieldwork in unsettling contexts. Through analyzing our interviews with these scholars, we find themes around the causes and consequences of unsettling fieldwork, and the coping strategies employed. We reflect on the often overlooked emotional and relational aspects of conducting and coping with unsettling fieldwork, and offer some suggestions for how scholars might support each other, especially given the increasing prevalence of organizational scholarship that pushes boundaries by engaging unconventional topics and settings.

Tackling society’s “grand challenges” is an increasingly important topic that many organizational scholars have started to turn towards. In this context, one question that has lately garnered a lot...

The institutional logics perspective has the explanatory power and potential to further contribute to our understanding of some of the most pressing societal concerns of our time. In this article, we develop the logics perspective along four analytical dimensions – macro-level positioning, contextuality, temporality and value plurality – which, we argue, can be leveraged to research and address grand challenges. We elaborate the currency of these dimensions in the context of the grand challenge of climate change. In doing so, we demonstrate the overall value of a logics perspective for engaging grand challenges.

This symposium invites consideration of the ways in which organizations interact with marginalized groups and to what effect. While such groups are, by definition, shunned by parts of society, ther...

In this paper, we examine why and how social enterprises may fail in foreign developing contexts despite promising conditions and initial success. Using data on Villages for Africa (VFA), a social ...

How do institutional paradoxes evolve? Although a growing body of research has described the organizational implications of a wide range of paradoxical pressures that are prevalent in organizationa...

While much research has focused on how institutional complexity can be managed at the organizational level, we know less about how individuals experience and cope with conflicting institutional pre...