This week we would like to introduce you to the work of Dr Laura Schmidt, a staff scientist in the Urologic Oncology Branch at the National Institutes of Health in Bethesda, USA.
Dr Schmidt was instrumental in the identification of the inherited kidney cancer genes FLCN (Nickerson et al., 2002) and MET (Schmidt et al., 1997), of which mutations cause BHD Syndrome and hereditary papillary renal cell carcinoma (HPRCC) respectively. Dr Schmidt was also involved in the identification of mutations in the VHL gene (Gnarra et al., 1994), which causes von Hippel-Lindau disease, and the FH gene (Toro et al., 2003), which leads to the development of hereditary leiomyomatosis and renal cell carcinoma (HLRCC).
Dr Schmidt’s work on BHD Syndrome focuses on elucidating the function of FLCN through several lines of investigation. One of these involved the identification of the Folliculin-interacting partners, FNIP1 and FNIP2 (Baba et al., 2006; Hasumi et al., 2008), which were also found to bind AMPK. It is through this association that it is now known that FLCN plays a role in cellular energy homeostasis.
Other methods used by Dr Schmidt to determine the function of FLCN include studying the phenotype of animal models that have knockout of FLCN, as well as genotype-phenotype correlation studies in patient groups. The latter is highlighted in a recent publication where large intragenic deletions and duplications were found in the FLCN gene (Benhammou et al., 2011). Although no genotype-phenotype correlation has been identified to date, this type of study could one day help to understand the different symptoms of BHD and their differential onset.
To find out more about Dr Schmidt and her work at the NIH, watch our video interview (with its accompanying transcript and audio-only files). Video interviews are also available for other members of the Urologic Oncology Branch, including Dr W. Marston Linehan, Dr Masaya Baba and Lindsay Middelton.
- Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell. 2002 Aug;2(2):157-64. PMID: 12204536
- Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997 May;16(1):68-73. PMID: 9140397
- Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh FM, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994 May;7(1):85-90. PMID: 7915601
- Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet. 2003 Jul;73(1):95-106. PMID: 12772087
- Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL, Furihata M, Oishi S, Zhen W, Burke TR Jr, Linehan WM, Schmidt LS, Zbar B. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15552-7. PMID: 17028174
- Hasumi H, Baba M, Hong SB, Hasumi Y, Huang Y, Yao M, Valera VA, Linehan WM, Schmidt LS. Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene. 2008 May 31;415(1-2):60-7. PMID: 18403135
- Benhammou JN, Vocke CD, Santani A, Schmidt LS, Baba M, Seyama K, Wu X, Korolevich S, Nathanson KL, Stolle CA, Linehan WM. Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dubé syndrome. Genes Chromosomes Cancer. 2011 Jun;50(6):466-77. PMID: 21412933
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.