title: H255Y and K508R missense mutations in tumour suppressor folliculin (FLCN) promote kidney cell proliferation.
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.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Department of Urology and Molecular Genetics, Yokohama City University, Yokohama, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hasumi
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hasumi
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Baba
authors.affiliation: Department of Applied Information Science, Tohoku University, Sendai, Japan.
authors.forename: Hafumi
authors.initials: H
authors.lastname: Nishi
authors.affiliation: Department of Molecular Pathology, Yokohama City University, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Furuya
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Cathy D
authors.initials: CD
authors.lastname: Vocke
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Lang
authors.affiliation: International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Irie
authors.affiliation: International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Esumi
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawahara
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University, Yokohama, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Isono
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University, Yokohama, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Makiyama
authors.affiliation: Pathology/Histotechnology Laboratory.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Warner
authors.affiliation: Pathology/Histotechnology Laboratory.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Haines
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Wei
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Berton
authors.initials: B
authors.lastname: Zbar
authors.affiliation: Laboratory Animal Sciences Program.
authors.forename: Herbert
authors.initials: H
authors.lastname: Hagenau
authors.affiliation: Laboratory Animal Sciences Program.
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University, Yokohama, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University, Yokohama, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Nakaigawa
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University, Yokohama, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yao
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Metwalli
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: W
authors.initials: W
authors.lastname: Marston Linehan
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D058249:Birt-Hogg-Dube Syndrome / Q000235:genetics* / Q000473:pathology; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006801:Humans; D007668:Kidney / Q000473:pathology; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C526060:Bhd protein, mouse; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins