Birt-Hogg-Dubé Syndrome

Toro, Jorge R.; Glenn, Gladys; Duray, Paul H.; Darling, Thomas N.; Weirich, Gregor; Zbar, Berton; Linehan, Marston; Turner, Maria L.

doi:10.1001/archderm.135.10.1195

Cited by 295 publications

(62 citation statements)

References 29 publications

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“…The nature of the follicular proliferations in many of the cancer-associated genodermatoses remains unclear and overlaps in histological pattern are not unusual. Birt-Hogg-Dubé patients have an increased risk of renal cell carcinoma [17]and do not have hyperkeratotic palmoplantar pits or cobblestoning of the oral mucosa [18]. …”

Section: Discussionmentioning

confidence: 99%

Cowden Syndrome – Diagnostic Skin Signs

2001

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Cowden syndrome is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. The most important clinical features include carcinomas of the breast and thyroid, and hamartomatous polyps of the gastrointestinal tract. There are characteristic mucocutaneous features which allow early recognition of the disease and are generally present before internal malignancies develop. We report on a woman in whom the diagnosis of Cowden syndrome was first made after she had been treated for both breast cancer and melanoma.

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Section: Discussionmentioning

confidence: 99%

Cowden Syndrome – Diagnostic Skin Signs

2001

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“…hamartoma syndrome ͉ renal cancer ͉ Birt-Hogg-Dubé ͉ tumor suppressor B irt-Hogg-Dubé (BHD) syndrome predisposes patients to develop hair follicle hamartomas, lung cysts, and an increased risk for renal neoplasia (1)(2)(3). BHD patients develop bilateral, multifocal renal tumors with a variety of histologies (4).…”

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confidence: 99%

Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling

Hong

Sharma³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Birt-Hogg-Dubé syndrome, a hamartoma disorder characterized by benign tumors of the hair follicle, lung cysts, and renal neoplasia, is caused by germ-line mutations in the BHD(FLCN) gene, which encodes a tumor-suppressor protein, folliculin (FLCN), with unknown function. The tumor-suppressor proteins encoded by genes responsible for several other hamartoma syndromes, LKB1, TSC1͞2, and PTEN, have been shown to be involved in the mammalian target of rapamycin (mTOR) signaling pathway. Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5 AMP-activated protein kinase (AMPK), a key molecule for energy sensing that negatively regulates mTOR activity. FNIP1 was phosphorylated by AMPK, and its phosphorylation was reduced by AMPK inhibitors, which resulted in reduced FNIP1 expression. AMPK inhibitors also reduced FLCN phosphorylation. Moreover, FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN may be regulated by mTOR and AMPK signaling. Our data suggest that FLCN, mutated in Birt-Hogg-Dubé syndrome, and its interacting partner FNIP1 may be involved in energy and͞or nutrient sensing through the AMPK and mTOR signaling pathways.hamartoma syndrome ͉ renal cancer ͉ Birt-Hogg-Dubé ͉ tumor suppressor B irt-Hogg-Dubé (BHD) syndrome predisposes patients to develop hair follicle hamartomas, lung cysts, and an increased risk for renal neoplasia (1-3). BHD patients develop bilateral, multifocal renal tumors with a variety of histologies (4). We mapped the BHD locus to chromosome 17p11.2 by linkage analysis in BHD kindreds (5, 6) and identified germ-line mutations in a gene with unknown function that is highly conserved (7,8). Twenty-two unique mutations predicted to truncate the BHD protein folliculin (FLCN), including a ''hot spot'' insertion͞deletion in a C 8 tract, were identified in 84% of BHD kindreds (9). Somatic ''second-hit'' mutations identified in BHD-associated renal tumors suggest a tumor-suppressor function for FLCN (10), underscored by loss of BHD mRNA expression in renal tumors from BHD patients (11).Recent studies suggest that several hamartoma syndromes may be linked through the convergent energy͞nutrient-sensing pathways involved in mammalian target of rapamycin (mTOR) regulation (12-15). These inherited syndromes are characterized by multiple hamartomas and an increased risk of cancer. Germ-line mutations have been identified in four causative genes: LKB1, responsible for Peutz-Jeghers syndrome (16-18), TSC1 and TSC2, responsible for tuberous sclerosis complex (TSC) (19), and PTEN, responsible for Cowden syndrome (20). Loss of gene function leads to dysregulation of mTOR, which regulates cell growth and size through stimulation of protein synthesis (15, 21, 22).BHD syndrome, also a hamartoma disorder, displays phenotypic similarities to TSC that have led to speculation that BHD may function in the pathway(s) signaling through mTOR (12,23). To ascertain FLCN function,...

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confidence: 99%

“…The BHD-related renal tumors, for example, appear to vary in histological features and have been reported as oncocytoma, papillary RCC and clear cell RCC (Roth et al, 1993;Toro et al, 1999). Lung diseases such as bronchiectasis, bronchospasm (Moreno et al, 1985) and spontaneous pneumothorax (Chung et al, 1996;Toro et al, 1999) have also been associated with BHD patients. In addition, colonic neoplasms (Rongioletti et al, 1989;Haimowitz et al, 1997), large connective tissue nevus (Weintraub and Pinkus, 1977), multiple lipomas, angiolipomas and parathyroid adenomas (Chung et al, 1996) have been described.…”

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confidence: 99%

Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2

et al. 2001

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Birt-Hogg-DubeÂ syndrome (BHD) is an autosomal dominant neoplasia syndrome characterized mainly by benign skin tumors, and to a lesser extent, renal tumors and spontaneous pneumothorax. To map the BHD locus, we performed a genome-wide linkage analysis using polymorphic microsatellite markers on a large Swedish BHD family. Evidence of linkage was identi®ed on chromosome 17p12-q11.2, with a maximum LOD score of 3.58 for marker D17S1852. Further haplotype analysis de®ned a *35 cM candidate interval between the two¯anking markers, D17S1791 and D17S798. This information will facilitate the identi®cation of the BHD gene, leading to the understanding of its underlying molecular etiology. Oncogene (2001) 20, 5239 ± 5242.

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Birt-Hogg-Dubé Syndrome

Cited by 295 publications

References 29 publications

Cowden Syndrome – Diagnostic Skin Signs

Cowden Syndrome – Diagnostic Skin Signs

Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling

Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2

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