Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome

Abstract

Birt-Hogg-Dubé (BHD) syndrome is a rare inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax. Recombination mapping in BHD families delineated the susceptibility locus to 700 kb on chromosome 17p11.2. Protein-truncating mutations were identified in a novel candidate gene in a panel of BHD families, with a 44% frequency of insertion/deletion mutations within a hypermutable C(8) tract. Tissue expression of the 3.8 kb transcript was widespread, including kidney, lung, and skin. The full-length BHD sequence predicted a novel protein, folliculin, that was highly conserved across species. Discovery of disease-causing mutations in BHD, a novel kidney cancer gene associated with renal oncocytoma or chromophobe renal cancer, will contribute to understanding the role of folliculin in pathways common to skin, lung, and kidney development.

Mutations in BHD and TP53 genes, but not in HNF1β gene, in a large series of sporadic chromophobe renal cell carcinoma

“…The entire coding region of BHD, TP53, and HNF1b was screened for mutations by direct sequencing (Nickerson et al, 2002;B. Bressac-de Paillerets, unpublished data;Rebouissou et al, 2005; see Supplementary Information).…”

“…The study of hereditary kidney cancer syndromes has led to the identification of kidney cancer-related genes that are also involved in sporadic RCC. Recently, germline BHD mutations were found in patients with Birt -Hogg -Dubé (BHD) syndrome (Nickerson et al, 2002), and a diverse spectrum of renal tumours have been described with somatic inactivation of BHD reported in BHD-related renal tumours (Khoo et al, 2002;Schmidt et al, 2005;Vocke et al, 2005). BHD promoter methylation has been reported in a subset of sporadic clear cell and chromophobe RCC, but somatic mutation of BHD in sporadic cases is rare (da Silva et al, 2003;Khoo et al, 2003).…”

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

“…Wilms tumor, also known as nephroblastoma, mostly affects children (Rivera and Haber, 2005). The majority of renal tumors occur sporadically, but a minority (B2%) of cases are associated with hereditary renal cancer diseases, such as the von Hippel-Lindau (VHL) syndrome (Latif et al, 1993), the hereditary papillary renal cancer (HPRC) syndrome (Schmidt et al, 1997), the hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome (Tomlinson et al, 2002) and the Birt-Hogg-Dube´(BHD) syndrome (Nickerson et al, 2002).…”

“…Furthermore, inactivation of VHL through methylation or loss of heterozygosity (LOH) occurs frequently in clear cell RCC (Herman et al, 1994;Moch et al, 1998;Brauch et al, 2000). The MET, FH and BHD genes have been identified to cause HPRC syndrome, HLRCC syndrome and BHD syndrome, respectively (Schmidt et al, 1997;Nickerson et al, 2002;Tomlinson et al, 2002) and their somatic mutations were also found in some sporadic counterparts of their hereditary tumor subtypes (Schmidt et al, 1999;Kiuru et al, 2002;Khoo et al, 2003).…”

Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma

“…However, the tumorigenic mechanisms for the sporadic RCCs that lack VHL gene inactivation and the multi-step processes involved in RCC progression remain unclear. Recently, the fumarate hydratase (FH) and Bert Hogg Dube (BHD) genes were identified by positional cloning as candidate tumor suppressor genes in RCC, but they appear to mainly participate in the development of hereditary human RCC (Nickerson et al, 2002;Tomlinson et al, 2002). To identify the genes inactivated in sporadic RCC, several studies attempted to clarify the methylation status of some cancer-related genes in RCC that are known to be epigenetically inactivated in other human cancers.…”