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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.

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