The adhesion GPCR latrophilin 3 (ADGRL3) has been associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) and substance use in human genetic studies. Knockdown in multiple species leads to hyperlocomotion and altered dopamine signaling. Thus, ADGRL3 is a potential target for treatment of neuropsychiatric disorders that involve dopamine dysfunction, but its basic signaling properties are poorly understood. Identification of adhesion GPCR signaling partners has been limited by lack of tools to acutely activate these receptors in living cells. Here, we designed a novel acute activation strategy to characterize ADGRL3 signaling by engineering a receptor construct in which we could trigger acute activation enzymatically. Using this assay, we found that ADGRL3 signals through G12/G13 and Gq, with G12/13 the most robustly activated. Gα12/13 is a new player in ADGRL3 biology, opening up unexplored roles for ADGRL3 in the brain. Our methodological advancements should be broadly useful in adhesion GPCR research.
Granular cell tumor (GCT) is a benign neuroectodermal tumor typically in the dermis or subcutis, although deep soft tissues and organs are occasionally involved. Multifocal GCTs are estimated to occur as many as 10% of patients. A 40-year-old female presented with multiple GCTs asynchronously involving various body sites including gastrointestinal, gynecologic, breast, urinary, and soft tissue systems. Pathologic examinations suggested benign GCTs. TruSight Tumor 170 next-generation sequencing (NGS) analysis performed on four resected tumors revealed subclonal mutation of PIK3CA p.H1047R identified in the esophageal GCT but not in the right vulva or the two cecal GCTs, suggesting that each is a primary tumor with a distinct genetic profile, rather than metastasis. PIK3CA p.H1047R is a common mutation in many cancers. Our benign GCT case demonstrates PIK3CA mutation with a low mutant allele frequency of 7%, which may represent an evolving subclone and might confer a more aggressive behavior.
Introduction: Celiac disease is an immune mediated reaction to the gluten protein. this disease primarily affects the small intestine.it occurs in population with genetic predisposition, usually resolves with gluten free diet regimen. it was reported the association between eosinophilic gastrointestinal diseases and celiac disease but in the following case will discuss patient with significant peripheral eosinophilia and celiac disease without Eosinophilic gastrointestinal disorder. Case Description/Methods: 45 years old male, with history of hypertension, who presented with progressively worsening intermittent colicky lower abdominal pain for the past 2 months. Associated with recurrent episodes of nausea and vomiting, and non-bloody watery diarrhea.Patient Labs were significant for Hemoglobin 12 gm/dL, WBC's 26,000 with 62% Eosinophils (16,500 /uL), Platelet of 332 Thou/uL. Peripheral blood smear was negative for parasites, stool was negative for parasites or bacterial infection. Patient went upper GI endoscopy that showed grade A reflux esophagitis, congestive gastropathy, Duodenitis, and non-bleeding gastric ulcer, Biopsies were obtained during the EGD. Pathology showed Duodenal mucosa with mild villous atrophy and focal increased intraepithelial lymphocytes suggestive of celiac disease,chronic gastritis, esophageal biopsy was negative for increased eosinophils. Patient was started on gluten free diet that was resulted in gradual resolution of his symptoms and also normal eosinophilic count after 1 month. (Figure ) Discussion: Patient with celiac disease can present with typical gastrointestinal symptoms such as diarrhea, weight loss, bloating, abdominal pain, and also non-gastrointestinal abnormalities such as abnormal liver function test, iron deficiency anemia, and it may be asymptomatic. In this case patient presented with typical symptoms but was associated with significant peripheral eosinophilia, without evidence eosinophilic gastrointestinal disorder.[3390] Figure 1. EGD showing stomach and duodenum.
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