Renal angiomyolipoma in Birt–Hogg–Dube syndrome: A case study supporting overlap with tuberous sclerosis complex

Dow, Eryn; Winship, Ingrid

doi:10.1002/ajmg.a.37952

Cited by 8 publications

(4 citation statements)

References 12 publications

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“…Increased nuclear TFEB is a hallmark of BHD syndrome 24 , which has some clinical similarity to TSC (both diseases are associated with chromophobe/oncocytic RCCs, benign facial skin tumors, and cystic lung disease) 48 , 49 . BHD is caused by mutations in FLCN , a known GAP for RAGC/D 20 – 22 .…”

Section: Discussionmentioning

confidence: 99%

TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism

et al. 2021

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Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). Transcription factor EB (TFEB), a master regulator of lysosome biogenesis, is negatively regulated by mTORC1 through a RAG GTPase-dependent phosphorylation. Here we show that lysosomal biogenesis is increased in TSC-associated renal tumors, pulmonary lymphangioleiomyomatosis, kidneys from Tsc2+/− mice, and TSC1/2-deficient cells via a TFEB-dependent mechanism. Interestingly, in TSC1/2-deficient cells, TFEB is hypo-phosphorylated at mTORC1-dependent sites, indicating that mTORC1 is unable to phosphorylate TFEB in the absence of the TSC1/2 complex. Importantly, overexpression of folliculin (FLCN), a GTPase activating protein for RAGC, increases TFEB phosphorylation at the mTORC1 sites in TSC2-deficient cells. Overexpression of constitutively active RAGC is sufficient to relocalize TFEB to the cytoplasm. These findings establish the TSC proteins as critical regulators of lysosomal biogenesis via TFEB and RAGC and identify TFEB as a driver of the proliferation of TSC2-deficient cells.

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Section: Discussionmentioning

confidence: 99%

TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism

et al. 2021

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“…Here we present a case of renal AML, a kidney neoplasm typically associated with TSC syndrome, in a patient with BHD. Previous case reports of AML in the setting of BHD in the literature posit on a phenotypic overlap between TSC and BHD, suggesting that renal AML may be a manifestation of BHD in those affected patients [ 13 , 15 ]. However, studies on renal AML have demonstrated that both TSC-associated and sporadic renal AMLs exhibit mutations and/or LOH in TSC1 or TSC2 [ 39 – 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…A number of case reports have reported overlapping phenotypic manifestations of BHD and TSC, including three cases of renal AML in patients with BHD [ 13 – 17 ]. Authors have then speculated on the overlap of the spectrum of these two syndromes due to similarities in phenotype and putative involvement of the implicated genes in the mTOR pathway.…”

Section: Introductionmentioning

confidence: 99%

Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dubé: chaperones in pathogenesis

et al. 2018

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Birt-Hogg-Dubé (BHD) is an autosomal dominant genetic syndrome caused by germline mutations in the FLCN gene that predisposes patients to develop renal tumors. Renal angiomyolipoma (AML) is not a renal tumor sub-type associated with BHD. AML is, however, a common phenotypic manifestation of Tuberous Sclerosis Complex (TSC) syndrome caused by mutations in either the TSC1 or TSC2 tumor suppressor genes. Previous case reports of renal AML in patients with BHD have speculated on the molecular and clinical overlap of these two syndromes as a result of described involvement of the gene products in the mTOR pathway. Our recent work provided a new molecular link between these two syndromes by identifying FLCN and Tsc2 as clients of the molecular chaperone Hsp90. Folliculin interacting proteins FNIP1/2 and Tsc1 are important for FLCN and Tsc2 stability as new Hsp90 co-chaperones. Here we present a case of sporadic AML as a result of somatic Tsc1/2 loss in a patient with BHD. We further demonstrate that FNIP1 and Tsc1 are capable of compensating for each other in the chaperoning of mutated FLCN tumor suppressor. Our findings demonstrate interconnectivity and compensatory mechanisms between the BHD and TSC pathways.

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“…This frameshift variant showed an extremely low frequency in the GnomAD population database (MAF = 0.000795%) and it was predicted to cause the Nonsense Mediated Decay (NMD) of the transcript, thus leading to haploinsufficiency. Also, the c.890_893delAAAG was already reported as pathogenic both in ClinVar database and in patients affected by BHD syndrome (Woodward et al, 2008;Kluger et al, 2010;Dow and Winship, 2016;Sprague and Landau, 2016).…”

Section: Reportmentioning

confidence: 90%

A pathogenic variant in the FLCN gene presenting with pure dementia: is autophagy at the intersection between neurodegeneration and cancer?

Bottillo,

Laino,

Azzarà

et al. 2024

Front. Neurosci.

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IntroductionFolliculin, encoded by FLCN gene, plays a role in the mTORC1 autophagy cascade and its alterations are responsible for the Birt–Hogg–Dubé (BHD) syndrome, characterized by follicle hamartomas, kidney tumors and pneumothorax.Patient and resultsWe report a 74-years-old woman diagnosed with dementia and carrying a FLCN alteration in absence of any sign of BHD. She also carried an alteration of MAT1A gene, which is also implicated in the regulation of mTORC1.DiscussionThe MAT1A variant could have prevented the development of a FLCN-related oncological phenotype. Conversely, our patient presented with dementia that, to date, has yet to be documented in BHD. Folliculin belongs to the DENN family proteins, which includes C9orf72 whose alteration has been associated to neurodegeneration. The folliculin perturbation could affect the C9orf72 activity and our patient could represent the first human model of a relationship between FLCN and C9orf72 across the path of autophagy.

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Renal angiomyolipoma in Birt–Hogg–Dube syndrome: A case study supporting overlap with tuberous sclerosis complex

Cited by 8 publications

References 12 publications

TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism

TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism

Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dubé: chaperones in pathogenesis

A pathogenic variant in the FLCN gene presenting with pure dementia: is autophagy at the intersection between neurodegeneration and cancer?

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