Exclusion of PTEN, CTNNB1, and PTCH as candidate genes for Birt-Hogg-Dube syndrome

Toro, Jorge R.

doi:10.1136/jmg.39.2.e10

Cited by 9 publications

(6 citation statements)

References 45 publications

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“…Our results further demonstrated that deficiency of BHD product FLCN led to activation of mTOR pathway in cystic cells, supporting the recent report and consolidating that FLCN is involved in mTOR pathway and mTOR may be downstream target of FLCN [21] . Interestingly, BHD is a member of the hamartoma syndrome family that includes Cowden syndrome (CD, affected gene PTEN ), Peutz-Jeghers syndrome (PJS, affected gene LKB1 ), and tuberous sclerosis complex (affected genes TSC1/TSC2 ) [14] , [15] , [16] . While PTEN, LKB1, and TSC1/2 have played pivotal roles in the mTOR pathway, our findings suggest that BHD protein FLCN, like other hamartoma syndrome–related proteins such as PTEN, LKB1, and TSC1/2, is an important component of the mTOR pathway, constituting a novel FLCN-mTOR signaling branch that regulates cell growth/proliferation, though FLCN may involve in other pathways.…”

Section: Discussionmentioning

confidence: 99%

“…As one of the hamartoma syndromes, BHD shares many clinical features (such as follicular hamartomas, mucosal fibromas, and internal malignancy) with Cowden syndrome (CD, affected gene PTEN ), Peutz-Jeghers syndrome (PJS, affected gene LKB1 ), and tuberous sclerosis complex (affected genes TSC1/TSC2 ) [14] , [15] , [16] . Of these, Cowden syndrome shares the most clinical features with BHD.…”

Section: Introductionmentioning

confidence: 99%

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Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia

et al. 2008

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The Birt–Hogg–Dubé (BHD) disease is a genetic cancer syndrome. The responsible gene, BHD, has been identified by positional cloning and thought to be a novel tumor suppressor gene. BHD mutations cause many types of diseases including renal cell carcinomas, fibrofolliculomas, spontaneous pneumothorax, lung cysts, and colonic polyps/cancers. By combining Gateway Technology with the Ksp-Cre gene knockout system, we have developed a kidney-specific BHD knockout mouse model. BHDflox/flox/Ksp-Cre mice developed enlarged kidneys characterized by polycystic kidneys, hyperplasia, and cystic renal cell carcinoma. The affected BHDflox/flox/Ksp-Cre mice died of renal failure at approximate three weeks of age, having blood urea nitrogen levels over tenfold higher than those of BHD flox/+/Ksp-Cre and wild-type littermate controls. We further demonstrated that these phenotypes were caused by inactivation of BHD and subsequent activation of the mTOR pathway. Application of rapamycin, which inhibits mTOR activity, to the affected mice led to extended survival and inhibited further progression of cystogenesis. These results provide a correlation of kidney-targeted gene inactivation with renal carcinoma, and they suggest that the BHD product FLCN, functioning as a cyst and tumor suppressor, like other hamartoma syndrome–related proteins such as PTEN, LKB1, and TSC1/2, is a component of the mTOR pathway, constituting a novel FLCN-mTOR signaling branch that regulates cell growth/proliferation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia

et al. 2008

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“…Our findings support that BHDS is associated with a spectrum of cutaneous hamartomas ranging from AF to PFF to FF. BHDS associated hamartomas should be distinguish it from other genodermatoses with an increased risk for internal malignancy 38. Recently, a BHD mutation was reported in one of three families with only trichodiscomas 8.…”

Section: Discussionmentioning

confidence: 99%

“…BHDS associated hamartomas should be distinguish it from other genodermatoses with an increased risk for internal malignancy. 38 Recently, a BHD mutation was reported in one of three families with only trichodiscomas. 8 However, two of the three families had an atypical presentation and most likely do not have BHDS.…”

Section: Discussionmentioning

confidence: 99%

BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports

Toro

Wei

Glenn

et al. 2008

Journal of Medical Genetics

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446

513

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Background:Birt–Hogg–Dubé syndrome (BHDS) (MIM 135150) is an autosomal dominant predisposition to the development of follicular hamartomas (fibrofolliculomas), lung cysts, spontaneous pneumothorax, and kidney neoplasms. Germline mutations in BHD are associated with the susceptibility for BHDS. We previously described 51 BHDS families with BHD germline mutations.Objective:To characterise the BHD mutation spectrum, novel mutations and new clinical features of one previously reported and 50 new families with BHDS.Methods:Direct bidirectional DNA sequencing was used to screen for mutations in the BHD gene, and insertion and deletion mutations were confirmed by subcloning. We analysed evolutionary conservation of folliculin by comparing human against the orthologous sequences.Results:The BHD mutation detection rate was 88% (51/58). Of the 23 different germline mutations identified, 13 were novel consisting of: four splice site, three deletions, two insertions, two nonsense, one deletion/insertion, and one missense mutation. We report the first germline missense mutation in BHD c.1978A>G (K508R) in a patient who presented with bilateral multifocal renal oncocytomas. This mutation occurs in a highly conserved amino acid in folliculin. 10% (5/51) of the families had individuals without histologically confirmed fibrofolliculomas. Of 44 families ascertained on the basis of skin lesions, 18 (41%) had kidney tumours. Patients with a germline BHD mutation and family history of kidney cancer had a statistically significantly increased probability of developing renal tumours compared to patients without a positive family history (p = 0.0032). Similarly, patients with a BHD germline mutation and family history of spontaneous pneumothorax had a significantly increased greater probability of having spontaneous pneumothorax than BHDS patients without a family history of spontaneous pneumothorax (p = 0.011). A comprehensive review of published reports of cases with BHD germline mutation is discussed.Conclusion:BHDS is characterised by a spectrum of mutations, and clinical heterogeneity both among and within families.

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“…As one of the hamartoma syndromes, BHD shares many clinical features (such as follicular hamartomas, mucosal fibromas, and internal malignancy) with Cowden syndrome (CD, affected gene PTEN), Peutz-Jeghers syndrome (PJS, affected gene LKB1), and tuberous sclerosis complex (affected genes TSC1/TSC2) [14,15,16]. Of these, Cowden syndrome shares the most clinical features with BHD.…”

Section: Introductionmentioning

confidence: 99%

Correction: Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia

Chen¹,

Futami²,

Petillo³

et al. 2008

PLoS ONE

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The Birt-Hogg-Dube ´(BHD) disease is a genetic cancer syndrome. The responsible gene, BHD, has been identified by positional cloning and thought to be a novel tumor suppressor gene. BHD mutations cause many types of diseases including renal cell carcinomas, fibrofolliculomas, spontaneous pneumothorax, lung cysts, and colonic polyps/cancers. By combining Gateway Technology with the Ksp-Cre gene knockout system, we have developed a kidney-specific BHD knockout mouse model. BHD flox/flox /Ksp-Cre mice developed enlarged kidneys characterized by polycystic kidneys, hyperplasia, and cystic renal cell carcinoma. The affected BHD flox/flox /Ksp-Cre mice died of renal failure at approximate three weeks of age, having blood urea nitrogen levels over tenfold higher than those of BHD flox/+ /Ksp-Cre and wild-type littermate controls. We further demonstrated that these phenotypes were caused by inactivation of BHD and subsequent activation of the mTOR pathway. Application of rapamycin, which inhibits mTOR activity, to the affected mice led to extended survival and inhibited further progression of cystogenesis. These results provide a correlation of kidney-targeted gene inactivation with renal carcinoma, and they suggest that the BHD product FLCN, functioning as a cyst and tumor suppressor, like other hamartoma syndrome-related proteins such as PTEN, LKB1, and TSC1/2, is a component of the mTOR pathway, constituting a novel FLCN-mTOR signaling branch that regulates cell growth/proliferation.

show abstract

Exclusion of PTEN, CTNNB1, and PTCH as candidate genes for Birt-Hogg-Dube syndrome

Cited by 9 publications

References 45 publications

Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia

Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia

BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports

Correction: Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia

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