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Hum Mol Genet. 2017 Jan 15;26(2):354-366. doi: 10.1093/hmg/ddw392.

H255Y and K508R missense mutations in tumour suppressor folliculin (FLCN) promote kidney cell proliferation.

Author information

1
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
2
Department of Urology and Molecular Genetics, Yokohama City University, Yokohama, Japan.
3
International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
4
Department of Applied Information Science, Tohoku University, Sendai, Japan.
5
Department of Molecular Pathology, Yokohama City University, Yokohama, Japan.
6
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
7
Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University, Yokohama, Japan.
8
Pathology/Histotechnology Laboratory.
9
Laboratory Animal Sciences Program.
10
Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Abstract

Germline H255Y and K508R missense mutations in the folliculin (FLCN) gene have been identified in patients with bilateral multifocal (BMF) kidney tumours and clinical manifestations of Birt-Hogg-Dubé (BHD) syndrome, or with BMF kidney tumours as the only manifestation; however, their impact on FLCN function remains to be determined. In order to determine if FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation leading to pathogenicity, we generated mouse models expressing these mutants using BAC recombineering technology and investigated their ability to rescue the multi-cystic phenotype of Flcn-deficient mouse kidneys. Flcn H255Y mutant transgene expression in kidney-targeted Flcn knockout mice did not rescue the multi-cystic kidney phenotype. However, expression of the Flcn K508R mutant transgene partially, but not completely, abrogated the phenotype. Notably, expression of the Flcn K508R mutant transgene in heterozygous Flcn knockout mice resulted in development of multi-cystic kidneys and cardiac hypertrophy in some mice. These results demonstrate that both FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation, but to different degrees. Based on the phenotypes of our preclinical models, the FLCN H255Y mutant protein has lost it tumour suppressive function leading to the clinical manifestations of BHD, whereas the FLCN K508R mutant protein may have a dominant negative effect on the function of wild-type FLCN in regulating kidney cell proliferation and, therefore, act as an oncoprotein. These findings may provide mechanistic insight into the role of FLCN in regulating kidney cell proliferation and facilitate the development of novel therapeutics for FLCN-deficient kidney cancer.

PMID:
28007907
PMCID:
PMC6075457
DOI:
10.1093/hmg/ddw392
[Indexed for MEDLINE]
Free PMC Article

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