The BHD Literature Database has been updated with 7 papers.
Yan et al., 2014 report that in FLCN-null mouse embryonic fibroblasts (MEFs), AMPK is constitutively activated, leading to increased PGC1a activity and a consequent increase in mitochondrial biogenesis and ROS production. This ultimately activates HIF signalling and leads to metabolic changes consistent with the Warburg Effect within FLCN-null cells. These changes were also observed in the FLCN-null FTC-133 thyroid carcinoma cell line. Readdition of FLCN into this cell line reduced the number of colonies formed in a soft agar assay, indicating that the metabolic transformation as a result of FLCN-loss provides these cells with a tumorigenic advantage. A nonphosphorylatable FLCN S62A mutant was unable to bind and inhibit AMPK, meaning that FLCN binding is required to inhibit AMPK. Immunohistochemical staining of a BHD kidney tumour showed increased expression of mitochondrial markers, HIF1a and HIF target genes, indicating that Warburg effect transformation contributes to tumour formation in BHD patients.
This study was partly funded by the Myrovlytis Trust.
Possik et al., 2014 report that FLCN deletion leads to constitutive activation of AMPK and a subsequent increase in autophagic flux and intracellular ATP levels. This leads to increased stress resistance and protection from apoptosis in both C. elegans nematodes, mouse embryonic fibroblasts, and the FLCN-null FTC-133 thyroid carcinoma cell line. Furthermore, inhibiting autophagy in FTC-133 lead to a reduction of colony formation in soft agar assays, suggesting that AMPK hyperactivity in response to FLCN-loss provides cells with a tumorigenic advantage.
This study was reviewed in the Editor’s Choice column in the 2nd May edition of Science.
Clinical research and case studies:
Murakami et al., 2014 report the cases of two patients – a 37 year old woman and a 35 year old man – who showed all three symptoms of BHD. Although these patients were clinically diagnosed with BHD, genetic testing was not performed to confirm the diagnosis. Retrospective analyses of 62 asian cases of BHD reported in the literature revealed that Asian patients are less likely to develop the skin symptoms of BHD, and there are only four reported cases of Asian patients developing all three symptoms of BHD. This paper is available to download from the BHD Articles Library: Clinical Research.
Johannesma et al., 2014 report the case of a 44 year old man who presented in clinic with urinary tract stones. Further examination revealed the presence of bilateral kidney tumours and a family history of pneumothorax. Genetic testing confirmed a diagnosis of BHD. This paper is available to download from the BHD Articles Library: Clinical Research.
Lopez-Garcia et al., 2014 describe the histological subtypes of trichodiscomas in a series of 42 American patients diagnosed with trichodiscomas between 1987 and 2013. They describe 11 histological subtypes, including some that have not been previously reported. They urge dermatologists to become familiar with these subtypes as some are associated with genetic syndromes, such as BHD and TSC.
Böer-Auer, 2014, reviews adnexal skin tumors, encompassing tumours of the hair follicle, and sebaceous, apocrine and eccrine glands. Such tumours can be symptoms of hereditary syndromes with other, more life threatening symptoms, such as BHD Syndrome, familial cylindromatosis and Muir-Torre Syndrome, making correct differentiation and diagnosis of these tumours essential. [Article in German]
Jawad et al., 2014 review the differences between the cystic lung diseases PLCH, LAM, BHD, LIP and LCDD, and cysts mimics, such as emphysema, as seen by high-resolution CT scanning.
To find out more, the latest version of the database is available to download here.