Molecular Genetics of B irt– H ogg– D ubé Syndrome

Abstract

Birt–Hogg–Dubé (BHD) syndrome is an autosomal dominant hereditary cancer disorder that predisposes at‐risk individuals to develop cutaneous fibrofolliculomas, pulmonary cysts, spontaneous pneumothoraces and kidney tumours. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD. BHD‐associated kidney tumours are most frequently hybrid oncocytic tumours or chromophobe renal carcinoma and show inactivation of the wild‐type FLCN allele either by somatic mutation or chromosomal loss, confirming that FLCN is a classic tumour suppressor. The FLCN protein interacts with two binding partners, FNIP1 and FNIP2, and with AMPK – an important negative regulator of mTOR. Studies in Flcn ‐deficient animal models support a role for FLCN in modulating mTOR activity. Emerging evidence suggests that FLCN interacts in a number of molecular pathways important for cell homeostasis that are often dysregulated in cancer including regulation of TFE3/TFEB transcriptional activity, amino acid‐dependent mTOR activation through Rag GTPases, TGF‐β signalling, PGC1‐α‐driven mitochondrial biogenesis and autophagy. Key Concepts Birt–Hogg–Dubé (BHD) syndrome is an autosomal dominant hereditary syndrome that predisposes at‐risk individuals to develop cutaneous fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax and increased risk for kidney tumours. Germline mutations in the FLCN gene on chromosome 17 are responsible for Birt–Hogg–Dubé syndrome. BHD‐associated kidney tumours are characterised by inactivation of the wild‐type copy of FLCN by somatic mutation or loss of chromosome 17p sequences confirming that FLCN is a classic tumour suppressor gene that follows the two‐hit model of tumourigenesis. Kidney tumours that develop in BHD‐affected individuals are most frequently hybrid oncocytic tumours or chromophobe renal carcinoma. The FLCN protein interacts with two novel binding partners, FNIP1 and FNIP2, and also with AMPK, an important negative regulator of mTOR. Studies in Flcn ‐deficient animal models support a role for FLCN in modulating mTOR activity. Emerging evidence suggests that FLCN may interact in a number of molecular pathways important for cellular homeostasis that are often dysregulated in cancer.

Birt-Hogg-Dubé syndrome with simultaneous hyperplastic polyposis of the gastrointestinal tract: case report and review of the literature

“…FLCN is currently the only gene known to be associated with BHD; however, the sensitivity of mutation detection is not 100%. In addition to the aforementioned mutation types, intragenic deletions and duplications are also catalogued in the Leiden Open Variation Database (https://databases.lovd.nl/shared/genes/FLCN) [39][40][41]. Thus, DNA-based diagnosis should ideally consist of sequence analysis and a test for large deletions or duplications, such as multiplex ligation-dependent probe amplification assays (MLPA) [42].…”