Expression of Birt–Hogg–Dubé gene mRNA in normal and neoplastic human tissues

Abstract

Birt-Hogg-Dubé (BHD) syndrome is an inherited autosomal genodermatosis characterized by hamartomas of the hair follicle called fibrofolliculomas and an increased risk for developing spontaneous pneumothorax, lung cysts and renal neoplasia. BHD was localized to chromosome 17p11.2 by linkage analysis in BHD families, and germline insertion/deletion and nonsense mutations in a novel gene were identified which were predicted to prematurely truncate the BHD protein, folliculin. No homology to other human proteins was found although folliculin was conserved across species. As a first step toward understanding the function of BHD in the cell and how BHD mutations can lead to the BHD phenotype, we measured the expression of BHD mRNA in normal and neoplastic human tissues by fluorescent in situ hybridization. BHD mRNA was expressed in a variety of tissues, including the skin and its appendages, the distal nephron of the kidney, stromal cells and type 1 pneumocytes of the lung, acinar cells of the pancreas and parotid gland, and epithelial ducts of the breast and prostate. In the brain, BHD mRNA was expressed in neurons of the cerebrum, and Purkinje cells in the cerebellum. BHD mRNA was also expressed in macrophage and lymphocytes in the tonsils and spleen. Tissues with reduced expression of BHD mRNA included heart, muscle and liver. BHD mRNA was expressed strongly in the proliferating epithelial strands of fibrofolliculomas, the cutaneous lesions characteristic of BHD, but not in renal tumors from BHD patients. These results indicate a wide expression pattern for BHD mRNA in many tissues, including skin, lung and kidney, which are involved in the BHD phenotype, and support a tumor suppressor role for BHD in renal cancer. Birt-Hogg-Dube´(BHD) syndrome is a genodermatosis inherited as an autosomal dominant trait. The disorder, first recognized in 1977, 1 is characterized by the presence of multiple skin papules on the head and neck accompanied by acrochordons (skin tags) and trichodiscomas. Histologically, the cutaneous papules consist of thin, epithelial strands originating from a central hair follicle with prominent associated connective tissue. These skin lesions were named fibrofolliculomas and considered to be hamartomas of the hair follicle. Since the original description of the disorder by Drs Birt, Hogg and Dubé, BHD families with characteristic dermatologic lesions and other phenotypic features have been reported including renal neoplasia, 2 lung cysts, and/or spontaneous pneumothorax. 3,4 Patients with fibrofolliculomas have a 50-fold increased risk for developing spontaneous pneumothorax, and a seven-fold increased risk for renal carcinoma. 5 Patients affected with BHD syndrome are predisposed to develop several different histologic types of renal carcinoma including clear cell, papillary and chromophobe renal carcinomas, renal oncocytomas and a hybrid tumor containing elements of both chromophobe renal carcinoma and renal oncocytoma. 6,7 The oncocytic hybrid renal tumor is the most common renal neoplasm found i...

Identification of the Genes for Kidney Cancer: Opportunity for Disease-Specific Targeted Therapeutics

“…In all cases, the germline BHD mutant allele was retained, and the wild-type BHD allele was lost. Consistent with these results, BHD mRNA expression was hardly detectable in BHD-associated renal tumors by in situ hybridization (87). Studies are currently under way to identify the BHD gene function and to determine how alteration of this gene leads to kidney cancer (Fig.…”

Lung Cysts, Spontaneous Pneumothorax, and Genetic Associations in 89 Families with Birt-Hogg-Dubé Syndrome

“…BHD mRNA is expressed in stromal cells and type I pneumocytes of the lung, suggesting that folliculin plays an important role in lung tissues (10). We have also reported that patients with BHDS are associated with the development of spontaneous pneumothorax (11).…”

Birt-Hogg-Dube Syndrome with Multiple Cysts and Recurrent Pneumothorax: Pathological Findings

“…The BHD gene codes a protein named folliculin, which is expressed in skin tissue, nephrons, and type I pulmonary alveolar epithelial cells (5). Its functions are unknown, although it is reported to be involved in cell growth (6) and as a cancer-inhibitory gene on the basis of renal tumor analysis (7,8). The BHD gene is composed of 14 exons, and exon 11 includes a hot spot that easily develops gene mutation due to the continuous residence of a cytosine base at C8.…”