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Volume 2, Issue 2, Pages 157-164 (August 2002) 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 Michael L. Nickerson, Michelle B. Warren, Jorge R. Toro, Vera Matrosova, Gladys Glenn, Maria L. Turner, Paul Duray, Maria Merino, Peter Choyke, Christian P. Pavlovich, Nirmala Sharma, McClellan Walther, David Munroe, Rob Hill, Eamonn Maher, Cheryl Greenberg, Michael I. Lerman, W.Marston Linehan, Berton Zbar, Laura S. Schmidt Cancer Cell Volume 2, Issue 2, Pages 157-164 (August 2002) DOI: 10.1016/S1535-6108(02)00104-6

Figure 1 Physical map of the BHD critical region on 17p11.2 defined by critical recombinants in Families 243, 210, and 216 showing location of the putative BHD gene A: The BAC tiling path is shown by black horizontal lines with arrowheads indicating directional read of completed sequence and Genbank accession numbers. BAC overlaps were confirmed by in silico and PCR methods. A single gap was spanned by exons of the COPS3 gene. Locations of polymorphic markers, shown in red, and genes, shown in blue, were confirmed in silico and by PCR amplification from BAC clones. Telo, telomere; cent, centromere. B: Critical recombinants identified in Family 243 (D17S2196), Family 210(CA109), and Family 216 (CA138) define the BHD minimal region to 700 kb. Nonrecombining region is in green. C: Location of 2 overlapping, uncharacterized mRNAs from melanoma (Genbank accession numbers BC015725 and BC015687) are shown within the 700 kb BHD candidate region. The BHD gene exon/intron structure with 14 coding exons is given. Cancer Cell 2002 2, 157-164DOI: (10.1016/S1535-6108(02)00104-6)

Figure 2 Mutation analysis of the BHD gene and cosegregation with disease in Families 200, 202, and 230 A: Family 200. a: Sequence analysis of somatic cell hybrid DNA from a BHD patient shows a C insertion in the (C)8 tract (nt 1733–1740) within exon 11 on the affected chromosome and wild-type (C)8 tract on the unaffected chromosome. b: The pedigree shows cosegregation of the C insertion mutation (C9) with disease (blue symbols, affected status). Individual 9 is an asymptomatic mutation carrier who carries the BHD affected haplotype and a history of spontaneous pneumothorax. B: Family 202. a: Sequence analysis of subcloned PCR product from a BHD affected individual shows the delAGinsC mutation (nt 1087–1088) in exon 7. b: The mutation produced a unique DHPLC heteroduplex peak (insert in black symbol) which cosegregated with disease (black symbols, affected status). Unaffected individuals (white symbols, unaffected status) show a wild-type homoduplex DHPLC peak (insert in white symbol). C: Family 230. a: Sequence analysis of exon 12 in BHD affected individuals shows a C→G mutation (nt 1844) which produces an in-frame terminaton at codon 463. b: The pedigree shows cosegregation of the mutation with disease (blue symbols, affected status). Cancer Cell 2002 2, 157-164DOI: (10.1016/S1535-6108(02)00104-6)

Figure 3 Mutation analysis of the BHD gene and cosegregation with disease in Family 228 A: Sequence analysis of a subcloned PCR product from a BHD affected individual shows a 28 bp duplication (nt 1378–1405) in exon 9. B: The pedigree shows cosegregation of the 28 bp allele with disease (blue symbols, affected status). PCR products from the exon 9 amplicon were electrophoresed on a 4%–20% polyacrylamide gradient gel to separate the 28 bp duplication allele (341 bp) from the wild-type allele (313 bp). Lane 1, 100 bp MW marker; lanes 2, 3, 5, 7, 8, and 9 represent affected individuals (blue symbols); lanes 4, 6, and 10 represent unaffected individuals (white symbols); lane 11, water blank. Cancer Cell 2002 2, 157-164DOI: (10.1016/S1535-6108(02)00104-6)

Figure 4 RNA tissue expression of BHD and amino acid sequence of the BHD protein, folliculin A: Northern blot analysis of BHD expression. A 3.8 kb transcript was detected in all tissues when a Northern blot (Origene) with 12 major tissues was hybridized with an exon 11 amplicon of the BHD gene, representing BC015725. The same size band was detected on a minor tissue Northern blot (Origene) which included skin, and a fetal blot (Clontech) containing lung, kidney, liver, and brain (data not shown). Hybridization of the blots with an exon 4 amplicon produced the same 3.8 kb transcript, representing BC015687 (data not shown). All lanes were loaded with 2 μg poly A+ RNA. B: Amino acid sequence of the BHD protein, folliculin, consisting of 579 amino acids. The locations of mutations identified in BHD patients are underlined in green. The predicted motifs in black boxes include a conserved SLS potential phosphorylation site (aa 128–130), a glutamic acid-rich coil-coil domain (aa 283–313), and an N-glycosylation site (aa 494–497). Three myristoylation sites are underlined in blue (aa 52–57, aa 266–271, aa 470–475). Regions of high homology in common in human, mouse, D. melanogaster, and C. elegans are underlined in black. Cancer Cell 2002 2, 157-164DOI: (10.1016/S1535-6108(02)00104-6)