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The prevalence of atopic diseases has increased abruptly in recent years in most Westernized societies, making the question why this happened the topic of a heated debate. The best paradigm available to date to explain this steep rise, the 'hygiene hypothesis', supports that it is the excess 'cleanliness' of our environments that has led to the decline in the number of infectious stimuli that are necessary for the proper development of our immune system. Recent findings support that it is the combined effect that not only pathogenic, but also non-pathogenic microorganisms, and even their structural components, can exert on the immune system that deters from the development of atopic responses. Adding to these results are intriguing new findings on the effect different gene polymorphisms can have on an individual's predisposition to allergic diseases. The most important linkages produced, to date, include those among the genes for IL-4, IL-13, HLA-DRB, TNF, LTA, FCER1B, IL-4RA, ADAM33, TCR alpha/delta, PHF11, GPRA, TIM, p40, CD14, DPP10, T-bet, GATA-3, and FOXP3 and allergic disorders. The two parallel research efforts, epidemiologic and genetic, are only recently starting to converge, producing fascinating results on the effect particular gene-environment interactions might have in the development of atopy. The most important lesson learned through this tremendous research effort is that not only a small number but thousands and millions of separate risk factors act in concordance in the production of the allergic phenotype.

Background Lowe syndrome (LS) is caused by loss-of-function mutations in the X-linked gene OCRL, which codes for an inositol polyphosphate 5-phosphatase that plays a key role in endosome recycling, clathrin-coated pit formation, and actin polymerization. It is characterized by congenital cataracts, intellectual and developmental disability, and renal proximal tubular dysfunction. Patients are also at high risk for developing glaucoma and seizures. We recently developed induced pluripotent stem cell (iPSC) lines from three patients with LS who have hypomorphic variants affecting the 3 ' end of the gene, and their neurotypical brothers to serve as controls. Methods In this study, we used RNA sequencing (RNA-seq) to obtain transcriptome profiles in LS and control neural progenitor cells (NPCs). Results In a comparison of the patient and control NPCs (n = 3), we found 16 differentially expressed genes (DEGs) at the multiple test adjusted p value (padj) < 0.1, with nine at padj < 0.05. Using nominal p value < 0.05, 319 DEGs were detected. The relatively small number of DEGs could be due to the fact that OCRL is not a transcription factor per se, although it could have secondary effects on gene expression through several different mechanisms. Although the number of DEGs passing multiple test correction was small, those that were found are quite consistent with some of the known molecular effects of OCRL protein, and the clinical manifestations of LS. Furthermore, using gene set enrichment analysis (GSEA), we found that genes increased expression in the patient NPCs showed enrichments of several gene ontology (GO) terms (false discovery rate < 0.25): telencephalon development, pallium development, NPC proliferation, and cortex development, which are consistent with a condition characterized by intellectual disabilities and psychiatric manifestations. In addition, a significant enrichment among the nominal DEGs for genes implicated in autism spectrum disorder (ASD) was found (e.g., AFF2, DNER, DPP6, DPP10, RELN, CACNA1C), as well as several that are strong candidate genes for the development of eye problems found in LS, including glaucoma. The most notable example is EFEMP1, a well-known candidate gene for glaucoma and other eye pathologies. Conclusion Overall, the RNA-seq findings present several candidate genes that could help explain the underlying basis for the neurodevelopmental and eye problems seen in boys with LS.