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.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals (47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age < or =30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma, and another individual from one of these families had collecting duct carcinoma of the kidney. The present study shows that mutations in FH are associated with HLRCC in North America. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. The present study also expands the histologic spectrum of renal tumors and FH mutations associated with HLRCC.
Birt-Hogg-Dubé syndrome, a hamartoma disorder characterized by benign tumors of the hair follicle, lung cysts, and renal neoplasia, is caused by germ-line mutations in the BHD(FLCN) gene, which encodes a tumor-suppressor protein, folliculin (FLCN), with unknown function. The tumor-suppressor proteins encoded by genes responsible for several other hamartoma syndromes, LKB1, TSC1͞2, and PTEN, have been shown to be involved in the mammalian target of rapamycin (mTOR) signaling pathway. Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5 AMP-activated protein kinase (AMPK), a key molecule for energy sensing that negatively regulates mTOR activity. FNIP1 was phosphorylated by AMPK, and its phosphorylation was reduced by AMPK inhibitors, which resulted in reduced FNIP1 expression. AMPK inhibitors also reduced FLCN phosphorylation. Moreover, FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN may be regulated by mTOR and AMPK signaling. Our data suggest that FLCN, mutated in Birt-Hogg-Dubé syndrome, and its interacting partner FNIP1 may be involved in energy and͞or nutrient sensing through the AMPK and mTOR signaling pathways.hamartoma syndrome ͉ renal cancer ͉ Birt-Hogg-Dubé ͉ tumor suppressor B irt-Hogg-Dubé (BHD) syndrome predisposes patients to develop hair follicle hamartomas, lung cysts, and an increased risk for renal neoplasia (1-3). BHD patients develop bilateral, multifocal renal tumors with a variety of histologies (4). We mapped the BHD locus to chromosome 17p11.2 by linkage analysis in BHD kindreds (5, 6) and identified germ-line mutations in a gene with unknown function that is highly conserved (7,8). Twenty-two unique mutations predicted to truncate the BHD protein folliculin (FLCN), including a ''hot spot'' insertion͞deletion in a C 8 tract, were identified in 84% of BHD kindreds (9). Somatic ''second-hit'' mutations identified in BHD-associated renal tumors suggest a tumor-suppressor function for FLCN (10), underscored by loss of BHD mRNA expression in renal tumors from BHD patients (11).Recent studies suggest that several hamartoma syndromes may be linked through the convergent energy͞nutrient-sensing pathways involved in mammalian target of rapamycin (mTOR) regulation (12-15). These inherited syndromes are characterized by multiple hamartomas and an increased risk of cancer. Germ-line mutations have been identified in four causative genes: LKB1, responsible for Peutz-Jeghers syndrome (16-18), TSC1 and TSC2, responsible for tuberous sclerosis complex (TSC) (19), and PTEN, responsible for Cowden syndrome (20). Loss of gene function leads to dysregulation of mTOR, which regulates cell growth and size through stimulation of protein synthesis (15, 21, 22).BHD syndrome, also a hamartoma disorder, displays phenotypic similarities to TSC that have led to speculation that BHD may function in the pathway(s) signaling through mTOR (12,23). To ascertain FLCN function,...
Birt-Hogg-Dubé syndrome (BHD), a genodermatosis characterized by multiple hamartomas of the hair follicle (fibrofolliculoma), predisposes individuals to an increased risk of developing renal neoplasms and spontaneous pneumothorax. Previously, we localized the BHD locus (also known as FLCN) to chromosome 17p11.2 by linkage analysis and subsequently identified germline mutations in a novel gene in probands from eight of the nine families with BHD in our screening panel. Affected members of five of the families inherited an insertion/deletion of a cytosine in a C8 tract in exon 11. This mutation was also identified by exon 11 screening in probands from 22 of 52 additional families with BHD and therefore represents a hypermutable "hotspot" for mutation in BHD. Here, we screened the remaining 30 families from this large BHD cohort by direct sequence analysis and identified germline BHD mutations in 84% (51/61) of all families with BHD recruited to our study. Mutations were located along the entire length of the coding region, including 16 insertion/deletion, 3 nonsense, and 3 splice-site mutations. The majority of BHD mutations were predicted to truncate the BHD protein, folliculin. Among patients with a mutation in the exon 11 hotspot, significantly fewer renal tumors were observed in patients with the C-deletion than those with the C-insertion mutation. Coding-sequence mutations were not found, however, in probands from two large families with BHD whose affected members shared their family's BHD-affected haplotype. Of the 53 families with BHD whose members inherited either a germline mutation or the affected haplotype, 24 (45%) had at least one member with renal neoplasms. Three families classified with familial renal oncocytoma were identified with BHD mutations, which represents the first disease gene associated with this rare form of renal neoplasm. This study expands the BHD-mutation spectrum and evaluates genotype-phenotype correlations among families with BHD.
Homozygous loss of BHD may initiate renal tumorigenesis in the mouse. The conditional BHD knockout mouse may be a useful research model for dissecting multistep kidney carcinogenesis, and rapamycin may be considered as a potential treatment for Birt-Hogg-Dubé syndrome.
Birt-Hogg-Dubé syndrome (BHD), an inherited autosomal genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal neoplasia, lung cysts, and spontaneous pneumothorax. To identify the BHD locus, we recruited families with cutaneous lesions and associated phenotypic features of the BHD syndrome. We performed a genomewide scan in one large kindred with BHD and, by linkage analysis, localized the gene locus to the pericentromeric region of chromosome 17p, with a LOD score of 4.98 at D17S740 (recombination fraction 0). Two-point linkage analysis of eight additional families with BHD produced a maximum LOD score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within a <4-cM distance between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to chromosome 17p, suggesting genetic heterogeneity for BHD. The BHD locus lies within chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy-number repeat elements, is unstable and that is associated with a number of diseases. Identification of the gene for BHD may reveal a new genetic locus responsible for renal neoplasia and for lung and hair-follicle developmental defects.
More children with chronic illnesses are attending school, and some of them struggle academically because of issues related to their health. School-based case management has been suggested as one strategy to improve the academic success of these children. This study tracked the academic, health, and quality of life outcomes for 114 children with asthma, diabetes, severe allergies, seizures, or sickle-cell anemia in 5 different school districts who were provided case management by school nurses. The children ranged in age from 5 to 19 years. At the end of the school year, children experienced an improvement in quality of life and gained skills and knowledge to manage their illness more effectively. Classroom participation, grades, and participation in extracurricular activities also increased for many children. The study provides evidence of the positive impact school nurses have on children with chronic illness and suggests ways they can measure the outcomes of their interventions.
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...
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