Browsing by Author "Kirmse, Brian"

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    Case Report: Ocular Toxocariasis: A Report of Three Cases from the Mississippi Delta
    (American Society of Tropical Medicine and Hygiene, 2019-03-11) Inagaki, Kengo; Kirmse, Brian; Bradbury, Richard S.; Moorthy, Ramana S.; Arguello, Irene; McGuffey, Charles D.; Tieu, Brian; Hobbs, Charlotte V.; Ophthalmology, School of Medicine
    Ocular toxocariasis can be vision threatening, and is commonly reported from tropical or subtropical regions. Knowledge of clinical manifestations from the United States, particularly in underserved areas such as the American South, is lacking. We report three cases of ocular toxocariasis in individuals from the Mississippi Delta, a rural community with prevalent poverty. Visual acuity was severely affected in two of the three cases. Increased awareness of ocular toxocariasis, which may have under-recognized frequency, will contribute to prompt diagnosis and treatment, which will ultimately improve patient health in the region.
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    TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila
    (Elsevier, 2021) Goodman, Lindsey D.; Cope, Heidi; Nil, Zelha; Ravenscroft, Thomas A.; Charng, Wu-Lin; Lu, Shenzhao; Tien, An-Chi; Pfundt, Rolph; Koolen, David A.; Haaxma, Charlotte A.; Veenstra-Knol, Hermine E.; Klein Wassink-Ruiter, Jolien S.; Wevers, Marijke R.; Jones, Melissa; Walsh, Laurence E.; Klee, Victoria H.; Theunis, Miel; Legius, Eric; Steel, Dora; Barwick, Katy E.S.; Kurian, Manju A.; Mohammad, Shekeeb. S.; Dale, Russell C.; Terhal, Paulien A.; van Binsbergen, Ellen; Kirmse, Brian; Robinette, Bethany; Cogné, Benjamin; Isidor, Bertrand; Grebe, Theresa A.; Kulch, Peggy; Hainline, Bryan E.; Sapp, Katherine; Morava, Eva; Klee, Eric W.; Macke, Erica L.; Trapane, Pamela; Spencer, Christopher; Si, Yue; Begtrup, Amber; Moulton, Matthew J.; Dutta, Debdeep; Kanca, Oguz; Undiagnosed Diseases Network; Wangler, Michael F.; Yamamoto, Shinya; Bellen, Hugo J.; Tan, Queenie K.G.; Pediatrics, School of Medicine
    Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.