RESUMO
Schizophrenia (SCZ) is a genetically heterogenous psychiatric disorder of highly polygenic nature. Correlative evidence from genetic studies indicate that the aggregated effects of distinct genetic risk factor combinations found in each patient converge onto common molecular mechanisms. To prove this on a functional level, we employed a reductionistic cellular model system for polygenic risk by differentiating induced pluripotent stem cells (iPSCs) from 104 individuals with high polygenic risk load and controls into cortical glutamatergic neurons (iNs). Multi-omics profiling identified widespread differences in alternative polyadenylation (APA) in the 3' untranslated region of many synaptic transcripts between iNs from SCZ patients and healthy donors. On the cellular level, 3'APA was associated with a reduction in synaptic density of iNs. Importantly, differential APA was largely conserved between postmortem human prefrontal cortex from SCZ patients and healthy donors, and strongly enriched for transcripts related to synapse biology. 3'APA was highly correlated with SCZ polygenic risk and affected genes were significantly enriched for SCZ associated common genetic variation. Integrative functional genomic analysis identified the RNA binding protein and SCZ GWAS risk gene PTBP2 as a critical trans-acting factor mediating 3'APA of synaptic genes in SCZ subjects. Functional characterization of PTBP2 in iNs confirmed its key role in 3'APA of synaptic transcripts and regulation of synapse density. Jointly, our findings show that the aggregated effects of polygenic risk converge on 3'APA as one common molecular mechanism that underlies synaptic impairments in SCZ.
RESUMO
Intraosseous hibernoma (IOH) mimicking osseous metastasis is a rare and little-known pitfall in nuclear medicine and radiology. Referring to a clinical case, we show imaging features in FDG-PET and CT as well as pathological characteristics and discuss MRI and differential diagnoses. A 73-year-old woman was assigned for an FDG-PET/CT examination after the incidental finding of a suspicious pulmonary nodule. The FDG-PET/CT examination detected a small slightly FDG-avid pulmonary nodule suspicious for malignancy and a small slightly sclerotic lesion with mild FDG-uptake in the upper pubic bone. Histopathology revealed an intraosseous hibernoma, a rare benign soft-tissue tumor arising from brown fat. In the sparse literature available, intraosseous hibernomas may or may not be positive on bone scans. As in our case, most are slightly sclerotic on CT but lytic lesions have also been described. On MRI, they are T1 hypointense to subcutaneous fat and hyperintense to skeletal muscle; they are usually T2 hyperintense and may show peripheral contrast enhancement. According to the literature, IOHs are mostly incidental findings with solitary lesions in the spine, pelvis, ribs, or, very rarely, in the extremities with low to moderately increased glucose metabolism. IOHs present as painless tumors in general; a few painful cases could be successfully treated with radiofrequency ablation or surgery. Differential diagnoses include metastases, lymphoma, fibrous dysplasia, and non-ossifying fibroma among others. Intraosseous hibernoma is a rare benign tumor that can mimic metastases in FDG-PET, CT, bone scan, and MRI. IOHs might be indistinguishable from metastases or malignant lesions, which makes a biopsy or follow-up mandatory in clinically relevant cases. Given the benign nature of IOHs, radiofrequency ablation or surgery is only an option in symptomatic cases.