Birt-Hogg-Dube Syndrome

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Birt-Hogg-Dubé (BHD) syndrome is a rare inherited autosomal dominant disorder caused by germline mutations in the folliculin (FLCN) gene (Nookala et al., 2012; Nickerson et al., 2008; Menko et al., 2012; Hartman et a., 2009). Patients with BHD initially develop fibrofolliculomas, typically as benign facial tumors, and lung cysts; whereby, increasing their risk to develop renal cell carcinoma (RCC) and pneumothorax (Nookala et a., 2012; Menko et al., 2012; Hartman et al., 2009). The majority of the BHD patient population contain germline mutations in FLCN exon 11, which is a hotspot for disease causing mutations. BHD research predicts mutations in FLCN results in a truncated folliculin protein lacking its c-terminal end, thus, suggestion the…show more content…
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase in which this catalytic subunit forms into two distinct multiprotein complexes, mTORC1 and mTORC2 (Laplante et al., 2009 and Bar-Peled et al., 2014). The two multiprotein complexes share many similarities, but are still distinct from one another. Both complexes regulate anabolic processes such as cell survival, metabolism and proliferation. However, mTORC2 is known to play a key role in cytoskeleton organization to regulate cellular spatial growth (Laplante et al., 2009 and? ). While they share many functions, only mTORC1 coordinates these anabolic functions with upstream inputs such as: growth factors, energy status, and amino acid availability. mTORC1 is composed of five components: mTOR, the catalytic subunit; regulator-associated protein of mTOR (RAPTOR), scaffolding subunit; mammalian lethal with Sec13 protein 8 (mLST8); and two endogenous kinase inhibitors proline-rich AKT substrate 40kDa (PRAS40) and DEP-domain-containing mTOR-interacting protein (DEPTOR) (Laplante et al., 2009 and Bar-Peled et al., 2014 (5,6,7,8,9) and more). In order to effectively control cellular physiology, mTORC1 activation triggers a downstream signaling cascade to control such anabolic processes as protein synthesis and ribosomal biogenesis (). However, mTORC1 signaling cascade is regulated by small GTPase Rheb located at the lysosome surface and functions as a mTORC1 kinase activity stimulator under its active GTP-bound state (Bar-Peeled et al., 2014). Nevertheless, Rheb is also negatively regulated by tuberous sclerosis complex (TSC) 1 and 2 by exerting is
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