Potential underlying genetic associations between keratoconus and diabetes mellitus.

Background Keratoconus (KC) is the most common ectatic corneal disease, characterized by significantly localized thinning of the corneal stroma. Genetic, environmental, hormonal, and metabolic factors contribute to the pathogenesis of KC. Additionally, multiple comorbidities, such as diabetes mellitus, may affect the risk of KC. Main Body Patients with diabetes mellitus (DM) have been reported to have lower risk of developing KC by way of increased endogenous collagen crosslinking in response to chronic hyperglycemia. However, this remains a debated topic as other studies have suggested either a positive association or no association between DM and KC. To gain further insight into the underlying genetic components of these two diseases, we reviewed candidate genes associated with KC and central corneal thickness in the literature. We then explored how these genes may be regulated similarly or differentially under hyperglycemic conditions and the role they play in the systemic complications associated with DM. Conclusion Our comprehensive review of potential genetic factors underlying KC and DM provides a direction for future studies to further determine the genetic etiology of KC and how it is influenced by systemic diseases such as diabetes.

Rare case: Ureteropelvic junction complication presenting with bilateral labial abscesses and urosepsis requiring nephrectomy.

Ureteropelvic junction obstruction (UPJO) is the most common cause of urinary tract obstruction in pediatric patients. Debates in management include ureteral stent versus nephrostomy tube placement prior to surgical correction if intervention is warranted. We present a female patient with left UPJO, diagnosed at 15-years-old, treated with ureteral stent placement. Stent removal two years later resulted in extensive complications, including retroperitoneal infection, labial abscesses, and nephrectomy. Management of UPJO in the pediatric population prior to surgical correction is not well-standardized. The severity of complications following the removal of the two-year-old stent suggests caution for placing ureteral stents without proper follow-up.

Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development.

A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, pheta1 and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient.This article has an associated First Person interview with the first author of the paper.

The transcription factor NeuroD2 coordinates synaptic innervation and cell intrinsic properties to control excitability of cortical pyramidal neurons.

KEY POINTS: Synaptic excitation and inhibition must be properly balanced in individual neurons and neuronal networks to allow proper brain function. Disrupting this balance may lead to autism spectral disorders and epilepsy. We show the basic helix-loop-helix transcription factor NeuroD2 promotes inhibitory synaptic drive but also decreases cell-intrinsic neuronal excitability of cortical pyramidal neurons both in vitro and in vivo. We identify two genes potentially downstream of NeuroD2-mediated transcription that regulate these parameters: gastrin-releasing peptide and the small conductance, calcium-activated potassium channel, SK2. Our results reveal an important function for NeuroD2 in balancing synaptic neurotransmission and intrinsic excitability. Our results offer insight into how synaptic innervation and intrinsic excitability are coordinated during cortical development. ABSTRACT: Synaptic excitation and inhibition must be properly balanced in individual neurons and neuronal networks for proper brain function. Disruption of this balance during development may lead to autism spectral disorders and epilepsy. Synaptic excitation is counterbalanced by synaptic inhibition but also by attenuation of cell-intrinsic neuronal excitability. To maintain proper excitation levels during development, neurons must sense activity over time and regulate the expression of genes that control these parameters. While this is a critical process, little is known about the transcription factors involved in coordinating gene expression to control excitatory/inhibitory synaptic balance. We show here that the basic helix-loop-helix transcription factor NeuroD2 promotes inhibitory synaptic drive but also decreases cell-intrinsic neuronal excitability of cortical pyramidal neurons both in vitro and in vivo as shown by ex vivo analysis of a NeuroD2 knockout mouse. Using microarray analysis and comparing wild-type and NeuroD2 knockout cortical networks, we identified two potential gene targets of NeuroD2 that contribute to these processes: gastrin-releasing peptide (GRP) and the small conductance, calcium-activated potassium channel, SK2. We found that the GRP receptor antagonist RC-3059 and the SK2 specific blocker apamin partially reversed the effects of increased NeuroD2 expression on inhibitory synaptic drive and action potential repolarization, respectively. Our results reveal an important function for NeuroD2 in balancing synaptic neurotransmission and intrinsic excitability and offer insight into how these processes are coordinated during cortical development.