Mutations in the Fumarate Hydratase Gene Cause Hereditary Leiomyomatosis and Renal Cell Cancer in Families in North America Jorge R. Toro, Michael L.

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Date of download: 6/2/2016 From: Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Topics Ann Intern Med. 1998;129(6): doi: /

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Mutations in the Fumarate Hydratase Gene Cause Hereditary Leiomyomatosis and Renal Cell Cancer in Families in North America Jorge R. Toro, Michael L. Nickerson, Ming-Hui Wei, Michelle B. Warren, Gladys M. Glenn, Maria L. Turner, Laveta Stewart, Paul Duray, Ousman Tourre, Nirmala Sharma, Peter Choyke, Pamela Stratton, Maria Merino, McClellan M. Walther, W. Marston Linehan, Laura S. Schmidt, Berton Zbar The American Journal of Human Genetics Volume 73, Issue 1, Pages 95-106 (July 2003) DOI: 10.1086/376435 Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical, histologic, and radiologic manifestations of HLRCC. A, Segmental distribution of leiomyomas in a 32-year-old man. Clinically, cutaneous leiomyomas presented as firm skin-colored to light-brown-colored papules and nodules. B, Histology of cutaneous leiomyoma. Leiomyomas were a proliferation of interlacing bundles of smooth-muscle fibers with a centrally located long blunt-edged nucleus in the dermis. C, Abdominal CT scan, showing the location of a renal tumor in the 32-year-old man shown in panel A. The resected neoplasm was a papillary type II renal cell carcinoma, as shown in panel D. D, Histologic findings of papillary type II renal cell carcinoma. There is a distinct papillary architecture. Cells had an abundant amphophilic cytoplasm and large nuclei with large inclusion-like eosinophilic nucleoli. Magnification × 200. The American Journal of Human Genetics 2003 73, 95-106DOI: (10.1086/376435) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 2 Age distribution at diagnosis of uterine fibroids (red) and reported age distribution at onset of cutaneous leiomyomas (blue) The American Journal of Human Genetics 2003 73, 95-106DOI: (10.1086/376435) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 3 Physical map of the FH critical region on 1q42.3 A, Ideogram of human chromosome 1q long arm with some markers at 1q42.3-43, with integrated genetic map (above) and physical map (below), showing locations of selected polymorphic markers. Cent. = centromere; Tel. = telomere. B, Expanded physical map. The BAC tiling path is shown by blue horizontal lines and GenBank clone ID numbers. BAC overlaps were confirmed in silico. A sequence gap is present in the 2.6-Mb region. C, Locations of known genes, shown within the 2.6-Mb region of FH. Seven known genes were identified and confirmed by searching public and private databases. D, FH exon-intron structure and mutations identified in the exonic sequence. The American Journal of Human Genetics 2003 73, 95-106DOI: (10.1086/376435) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 4 FH mutations in patients with HLRCC. Sequencing chromatograms of genomic DNA from control subjects and patients are shown at left (arrows indicate the position of the identified nucleotide changes), and pedigrees are shown at right (asterisks indicate history of renal cancer). The delA at nucleotide 1162 (A), a delG at nucleotide 1339 (D), a delGC at nucleotides 780 and 781 (E), and an 8-bp duplication at nucleotides 1300–1307 (F) cause shifts in the reading frame that lead to a stop codon downstream and truncate the corresponding protein; a missense mutation, G569A (B), changes an arginine to a histidine at codon 190, and another missense mutation, C823T (C), changes a histidine to a tyrosine at codon 275. Sequences containing insertions and deletions are derived from subcloned alleles from affected patients. The American Journal of Human Genetics 2003 73, 95-106DOI: (10.1086/376435) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 4 FH mutations in patients with HLRCC. Sequencing chromatograms of genomic DNA from control subjects and patients are shown at left (arrows indicate the position of the identified nucleotide changes), and pedigrees are shown at right (asterisks indicate history of renal cancer). The delA at nucleotide 1162 (A), a delG at nucleotide 1339 (D), a delGC at nucleotides 780 and 781 (E), and an 8-bp duplication at nucleotides 1300–1307 (F) cause shifts in the reading frame that lead to a stop codon downstream and truncate the corresponding protein; a missense mutation, G569A (B), changes an arginine to a histidine at codon 190, and another missense mutation, C823T (C), changes a histidine to a tyrosine at codon 275. Sequences containing insertions and deletions are derived from subcloned alleles from affected patients. The American Journal of Human Genetics 2003 73, 95-106DOI: (10.1086/376435) Copyright © 2003 The American Society of Human Genetics Terms and Conditions