MGMT is responsible for the detection and repair of DNA damage caused by alkylating agents. If the damage is severe enough then the repair mechanism is bypassed, and to prevent transition mutations being propagated after DNA replication, apoptosis is initiated by MGMT via MAPO1, as the authors suggest.

So how is this relevant to BHD Syndrome? MAPO1 also goes by the name FNIP2. The relationship between FNIP2 and FLCN is not fully understood but could FLCN have any role in regulating FNIP2 activity in apoptosis induction in response to alkylating damage? Could this facet contribute to the accumulation of genetic instability in tissues with high cell turnover and metabolism (i.e. the kidneys) and could we speculate that this could contribute to the development of malignant tumours in the kidneys of BHD patients as opposed to any other organ since the kidneys are exposed to high levels of external chemicals due to their role in filtering urine?

Komori, K., Takagi, Y., Sanada, M., Lim, T.-H., Nakatsu, Y., Tsuzuki, T., Sekiguchi, M., Hidaka, M. A novel protein, MAPO1, that functions in apoptosis triggered by O(6)-methylguanine mispair in DNA. Oncogene 28: 1142-1150, 2009.

The multi-step model for tumourigenesis proposes that the tumourigenic growth of malignant cells from normal tissue is preceded by the accumulation of genetic errors in a sequential fashion, where each step provides a positive growth advantage to the nascent tumour cells, allowing them to break free from the normal regulatory constraints that determine normal growth and differentiation. Habib et al, (2010)* have shown that rapamycin treated HK2 cells, mouse Tsc-deficient cells and human VHL-deficient cells leads to increased protein and promoter activity of the DNA repair enzyme OGG1 and that this mediated via an increase in  expression of the transcription factor, NF-YA. This increase in OGG1 activity is thought to suppress the development of further tumours in treated cells and the authors speculate that a rapamycin-mediated mechanism of enhancing DNA repair in cancer cells  may explain the inhibition of further tumourigenic growth for as long as rapamycin is applied.

DNA repair enzymes such as OGG1 repair damage to DNA bases caused by oxidative damage, which may occur because of normal aerobic metabolism or exposure to external environmental carcinogens. Whilst such damage itself is not immediately pathogenic, it results in a mutator phenotype since the ‘increasing impairment in DNA repair contributes to the genomic instability, and consequently increases the risk of cancer’. Indeed, a familial colorectal polyposis syndrome know as MAP is  caused by bialleic inactivation of the DNA repair enzyme MUTYH, so as ‘family’ of proteins, their significance in cancer aetiology is not to be underestimated.

Given the phenotypic overlap between BHD Syndrome, VHL and TSC, as well as the role implicated for FLCN in mTOR signalling (and subsequent therapeutic benefit of rapamycin analogs) I wonder whether DNA repair enzymes may have a similar role in BHD associated tumourigenesis.

*Habib SL, et al. Novel mechanism of reducing tumourigenesis: Upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition.Eur J Cancer. 2010 Jul 23.

Sun A et al, 2010. Liverbase: a comprehensive view of human liver biology. J Proteome Res. Jan;9(1):50-8.

The large growth on the right kidney was benign. Are others in a similar position? Their lungs are clear and they have no other symptoms or difficulties.

TAZ, a transcriptional co-activator with a PDZ-binding motif (also called WWTR1) is a 14-3-3-binding molecule. TAZ acts as a co-activator for several transcription factors as well as a modulator of membrane-associated PDZ domain-containing proteins, but its physiological roles remain unknown.

The coexistence of renal and pulmonary defects observed in TAZ-deficient mice hasn’t been observed before. TAZ may have a role in a pathway common to pulmonary and renal development and so further investigation could uncover a common mechanism for organogenesis and pathogenesis of human diseases. That said, is this phenotype limited to a single mouse model and due to the specific genetic background or could the similarities observed between this phenotype and BHD Syndrome suggest any mechanistic overlap between TAZ and FLCN?

Makita R et al, 2008. Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ. Am J Physiol Renal Physiol. Mar; 294(3):F542-53.

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The site will open up in a new window and can be navigated in its entirety in the translated language. Because we are using a third party application we aren’t responsible for quality of the translated sites but welcome your feedback on the quality of the translations and suggestions for other languages. We hope that this function will allow us to appeal to a broader audience.

However, a recent paper by Maffe et al, in Clinical Genetics presents the results of a clinical study of unrelated individuals presenting with the non-dermatological symptoms of BHD Syndrome, and amongst its conclusion the authors state that ‘parotid oncocytomas should be considered as a BHDS component manifestation, in addition to cutaneous, kidney, and pulmonary lesions’ because of its frequency amongst the cohort studied. Other symptoms associated with BHD Syndrome have been discussed in the literature and can be found summarised here. I think clinically, an awareness of all the relevant symptoms is essential for a timely diagnosis of BHD Syndrome.

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