CENOMICS6,565-567(1990)
SHORT COMMUNICATION Confirmation
of Linkage in von Hippel-Lindau
Disease
JEFFERY M. VANCE, KENT W. SMALL, MARY A. JONES, JEFFREY M. STAKH, LARRY H. YAMAOKA, ALLEN D. ROSES, WU-YEN HUNG, AND MARGARET A. PERICAK-VANCE Department
of Medicine,
Division of Neurology, ReceivedAugust18,
Duke University Medical 1989;revised
Academic
Press,
12, 1989
sampled, there were 11 living affected individuals. A subsection of one family (DUK 771) was included in Seizinger’s original report of linkage to RAFl. However, additional family members in DUK 771 have been examined subsequent to the Seizinger et al. paper and their DNA banked. Patients were examined by both a neurologist and an ophthalmologist. Diagnosis of VHL was made on the basis of the criteria stated by Melmon and Rosen (1964; Huson et al., 1986). DNA was isolated, digested, and hybridized using standard methodology as previously reported (PericakVance et al., 1988b). RAF1 (probe ~627) (Bonner et al., 1989) recognizes both a TaqI (PIC 0.31) andBgl1 (PIC 0.37) polymorphism. The THRB cDNA clone, pHeAl2 (Weinberger et al., 1986), recognizes three separate polymorphisms, BamHI (PIC 0.33) and two EcoRV loci (PICs 0.27 and 0.30, respectively) (Bale et al., 1988). VHL was analyzed as an autosomal dominant trait with age-dependent penetrance. Patients with a normal medical history (whether recently examined or not) were included in the analysis by assigning a probability of being affected using an age of onset curve based on the data of Go et al. (1984) and our own data. Data were processed via the PEDIGENE system (Haynes et al., 1988; Pericak-Vance et al., 1988a). The linkage analysis used the LINKAGE computer program package (Version 4.7) (Lathrop et aZ., 1984). The MLINK subprogram of the LINKAGE package was used for the two-point analyses assuming equal recombination in males and females (Jonathan Haines, personal communication). Haplotypes were constructed from the various polymorphisms for the two markers. The marker frequencies used in the analyses were as previously reported (Seizinger et al., 1988, Bale et al., 1988). A gene frequency of 0.0001 was assumed for the VHL gene. In addition, the program HOMOG (Ott, 1985) was used to test for the existence of heterogeneity in VHL by combining our data with the published RAF1 data.
Von Hippel-Lindau (VHL) disease was initially reported to be linked to the RAF1 oncogene (3~25). We have ascertained and sampled two large multigenerational VEIL families for linkage studies, in order to confirm the localization of the VHL gene as a prelude to fine mapping studies. The probes used in the analysis were ~627 (RAFl) and pHeAl2 (thyroid hormone receptor B) (3~24.1-3~22). VHL was analyzed as an autosomal dominant trait with age-dependent penetrance. The maximum lod score combining both families was z(a) = 2.16 at 8 = 0.0 for RAF1 and z(8) = 2.20 at 8 = 0.05 for thyroid hormone receptor B. Multipoint analysis using the RAF1 and thyroid hormone receptor B loci resulted in a peak lod score of 3.1 conflrming linkage of VHL to this region of chromosome 3. However, the position of VHL relative to the two loci could not be established with certainty. Q 1990
November
Center, Durham, North Carolina 27710
Inc.
Von Hippel-Lindau disorder (VHL) is a rare, autosomal dominant disease characterized by formation of hemangioblastomas in the retina, CNS, and viscera including the kidneys, adrenals, and pancreas. In addition, an increased frequency of pheochromocytoma, renal cell carcinoma, and hypernephromas is associated with the disorder. Age of onset is variable, but development of symptoms is usually in early adulthood (Huson et al., 1986). Seizinger et al. (1988) reported linkage of VHL to RAFl, an oncogene mapping to chromosome 3~25 (Banner et al., 1989), with z(e) = 4.38 at 8 = 0.11. The present report confirms the linkage of VHL to the region of the RAF1 oncogene, inclusive of the thyroid hormone receptor B gene (THRB), located on chromosome 3~24.1-3~22 (McAlpine et al., 1989). Thirty-five individuals from two large VHL families were obtained through Duke University Medical Center and blood was obtained for DNA storage and creation of permanent lymphoblastoma cell lines. Of those 565
All
Copyright 0 1990 rights of reproduction
0&3&%7543/SO $3.00 by Academic Press, Inc. in any form reserved.
566
SHORT
COMMUNICATION
In order to maximize the information available in each pedigree, and potentially gain information on marker order, multipoint analysis using the LINKMAP subprogram of the LINKAGE package was employed. Both the RAF1 and THRB loci were used in the analyses. THRB was fixed at a map distance of 0.13 Morgans from RAF1 (Jonathan Haines, personal communication); Kosambi’s mapping function was used to explain the differences between genetic distance and recombination (Lathrop et al., 1984). VHL was moved sequentially through all positions of the map and the corresponding likelihood was calculated. Multipoint lod scores, i.e., log,, (likelihood difference) of VHL being unlinked versus VHL lying at various positions on the map, were obtained (Keats and Ott, 1989). Results of the two-point analysis showed that family DUK 771 was uninformative for RAFl. Therefore, although a subsection of this family had been previously examined by Seizinger et al. (1988), the family was not contributory to the overall lod score obtained from RAF1 in their analysis and thus could be incorporated into the present analysis. The maximum lod scores combining both families in the two-point analysis were z(e) = 2.16 at 4 = 0.0 for RAF1 and z(& = 2.20 at 8 = 0.05 for THRB. Combining our RAF1 data with those of Seizinger et at. and using the HOMOG computer program gave no evidence for genetic heterogeneity in VHL. The maximum likelihood estimate of y, the proportion of linked families, was 1.0 with a lower 95% confidence limit of 0.8. The results of the multipoint analysis are shown in Fig. 1. A peak lod score of 3.1 was found when VHL was placed at 0.0 recombination with the RAF1 locus. The position of VHL relative to the two loci could not be established with certainty, as the odds favoring this position are only 3:l over a position distal to THRB. In summary, we confirm the linkage of VHL to RAF1 initially reported by Seizinger et al. (1988) and additionally report linkage of VHL to THRB. This supports the location of the VHL gene to the 3p22-pter region, as was found in the Seizinger et al. study. Clinically, VHL appears to demonstrate variable expressivity but there is no evidence at this time to suggest clinical heterogeneity. Heterogeneity analysis of the pooled linkage data supports this hypothesis. The region of 3p continues to be an intriguing area containing multiple loci which appear associated with several oncogene entities including renal cell (Cohen et al., 1984) and small cell carcinoma (Johnson et al., 1988). Because of the extensive periodic radiographic and clinical screening needed to evaluate at-risk individuals for VHL, DNA probes for accurate carrier detection would be a great benefit to family members. We continue work on developing further probes in this region to flank the VHL gene.
4 i 3-
2
2-
8 5
l-
TnAB\\ 0-l
RAF't
FIG. 1. Results of the multipoint analysis RAF1 and THRB. Kosambi’s mapping function recombination fractions into map distances.
between VHL and was used to convert
ACKNOWLEDGMENTS The authors thank Nigel Walker, Fiona Francis, John Pufky, Kenneth Wilkinson, Edward Hanson, and Guillermo Arana for their excellent technical contributions to this work; Peggy Pate and Helen Harbett for data processing; Carol Haynes and Marcy Speer for computer expertise, and Carolyn Turner for manuscript preparation. THRB was kindly provided by C. Weinberger; RAF1 was obtained from the ATCC. This project was supported in part by NIH Grant NS26630, the Leadership and Excellence in Alxheimer’s Disease (LEAD) Award AG07992, and CIDA Grant NS01289.
REFERENCES 1. BALE, A. E., USALA, S., WEINBERGER, AND MCBRIDE, the hc-(ERBA) RFLP. Nucleic 2.
C., WEINTRAUB, B. D., 0. W. (1988). A cDNA probe (Phe Al2) from gene on chromosome 3 detects a high frequency Acids Res. 16: 7756-7756.
BONNER, T., O’BRIEN, S. J., NASH, W. G., RAPP, U. R., MORTON, C. C., AND LIZDER, P. (1989). The human homologs of the raf (mil) oncogene are located on human chromosome 3 and 4. Scknce233:71-74.
3.
COHEN, A. J., LI, F. P., BERG, S., MARCHETTO, D. J., TSAI, S., JACOBS, S. C., AND BROWN, R. S. (1994). Hereditary renal cell carcinoma associated with a chromosomal translocation. N. Engl, J. Med. 301: 592-595.
4.
CONNEXLLY, P. M., EDWARDS, J. H., KIDD, K.-K., LALOUELJ.-M., MORTON, N. E., OTT, J., AND WHITE, R. (1985). Report of the committee on methods of linkage analysis and reporting. Cytogenet. Cell Genet. 40: 356-359.
5.
Go, R. C. P., LAMIELL, J. M., HSIA, Y. E., YUEN, J. W. M., AND PALK, Y. (19&t). Segregation and linkage analysis of von Hippel-Lindau Disease among 220 descendants from one kindred. Amer. J. Hum. Genet. 36: 131-142.
SHORT
COMMUNICATION
6. HAYNES, C. S., PIWXK-VANCE, M. A., HUNG, W-Y., DEu’lXCH, D. B., AND ROSES, A. D. (1988). PEDIGENE-A computerized data collection and enalydr system for genetic laboratories. Amer. J. Hum. Gent%. 43: A146. I. HUSON, S. M., HARPER, P. S., HOIJRIHAN, M. D., COLE, G., WEEKS, R. D., AND COMPSMN, D. A. S. (1986). Cerebellar heemangioblestoma and von Hippel-Lindeu Disease. Brain 109: 1297-1310. 8. JOHNSON, B. E., SAKAGUCHI, A. Y., GAZDAE, A. F., MINNA, J. D., BURCH, D., MARSHALL, A., AND NAYIX% S. L. (1968). Restriction fragment length polymorphism studies show consistent loss of chromosome 3p alleles in smell cell lung cancer patients tumors. J. Clin. Znuest. 82: 502-507. 9. KEATS, B., AND OTT, J. (1989). Report of the committee on linkage and gene order. Cytogenet. Cell Genet. 51: 459-502. 10. LATHROP, G. M., LALOUEL, J. M., JULIER, C., AND OTT, J. (1984). Strategies for multilocus linkage analysis in humans. Proc. Natl. Acad. Sci. USA 81: 3443-3446. 11. MCALPINE, P. J., SHOWS, T. B., BOUCHEIX, C., STRANC, L. C., BEVENT, T. G., PAKSTIS, A. J., AND DO~TE, R. c. (1989). Report of the Nomenclature Committee and the 1989 Catalog of Mapped Genes. Cytogenet. Cell Genet. 51: 13-66. 12. MELMON, K. L., AND ROSEN, S. W. (1964). Lindau’s disease: Review of the literature and study of a large kindred. Amer. J. Med. 36: 595-617.
567
13. m, J. (1985). “Analysis of Human Genetic Linkage” pp. 105119. Johns Hopkins University Press, Baltimore. 14. PERICAK-VANCE, M. A., HUNG, W. Y., YAMAOKA, L., HAYNES, C., BARTLETT, R. J., VANCE, J. M., LEE, J., SIDDIQUE, T., GASKELL, P. C., STAJICH, J., AND ROSES, A. D. (1988s). Systematic gene mapping in man: Date management considerations. Awt. Paedintr. J. Sup& 87-69. 15. PEFUCAK-VANCE,M. A., YAMAOKA, L. H., HAYNES, C. S., SPEER, M. C., HAINES, J. L., GASKELL, P. C., HUNG, W. Y., CLARK, C. M., HEYMAN, A. L., TF~OFATTER, J. A., EISENMENGER, J. P., GILBERT, J. R., LEE, J. E., ALBERTS, M. J., DAWSON, D. V., BARTLETT, R. J., EARL, N. L., SIDDIQUE, T., VANCE, J. M., CONNEALLY, P. M., AND ROSES, A. D. (1988b). Genetic linkage studies in Alzheimer’s Disease families. Erp Neural. 102: 271279. 16. SEIZINGER, B. R., ROULEAU, G. A., OZELJXJS,L. J., LANE, A. H., FARMER, G. E., LAMIELL, J. M., HAINES, J., YUEN, J. W. M., COLLINS, D., MAJOOR-KRAKAUER, D., BONNER, T., MATHEW, C., RUBENSTEIN, A., HALPERIN, J., MCCONKIE-ROSELL, A., GREEN, J. S., TROFATTER, J. A., PONDER, B. A., EIERMAN, L., BOWMER, M. I., AND SCHIMKE, R. (1988). Von Hippel-Lindeu disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature (London) 332: 266-269. 17. WEINBERGER, C., THOMPSON, C. C., ONG, E. S., LEBO, R., GRUOL, D. J., AND EVANS, R. M. (1986). The c-erb-A gene encodes a thyroid hormone receptor. Nature (London) 324: 641644.
SHORT COMMUNICATION Confirmation
of Linkage in von Hippel-Lindau
Disease
JEFFERY M. VANCE, KENT W. SMALL, MARY A. JONES, JEFFREY M. STAKH, LARRY H. YAMAOKA, ALLEN D. ROSES, WU-YEN HUNG, AND MARGARET A. PERICAK-VANCE Department
of Medicine,
Division of Neurology, ReceivedAugust18,
Duke University Medical 1989;revised
Academic
Press,
12, 1989
sampled, there were 11 living affected individuals. A subsection of one family (DUK 771) was included in Seizinger’s original report of linkage to RAFl. However, additional family members in DUK 771 have been examined subsequent to the Seizinger et al. paper and their DNA banked. Patients were examined by both a neurologist and an ophthalmologist. Diagnosis of VHL was made on the basis of the criteria stated by Melmon and Rosen (1964; Huson et al., 1986). DNA was isolated, digested, and hybridized using standard methodology as previously reported (PericakVance et al., 1988b). RAF1 (probe ~627) (Bonner et al., 1989) recognizes both a TaqI (PIC 0.31) andBgl1 (PIC 0.37) polymorphism. The THRB cDNA clone, pHeAl2 (Weinberger et al., 1986), recognizes three separate polymorphisms, BamHI (PIC 0.33) and two EcoRV loci (PICs 0.27 and 0.30, respectively) (Bale et al., 1988). VHL was analyzed as an autosomal dominant trait with age-dependent penetrance. Patients with a normal medical history (whether recently examined or not) were included in the analysis by assigning a probability of being affected using an age of onset curve based on the data of Go et al. (1984) and our own data. Data were processed via the PEDIGENE system (Haynes et al., 1988; Pericak-Vance et al., 1988a). The linkage analysis used the LINKAGE computer program package (Version 4.7) (Lathrop et aZ., 1984). The MLINK subprogram of the LINKAGE package was used for the two-point analyses assuming equal recombination in males and females (Jonathan Haines, personal communication). Haplotypes were constructed from the various polymorphisms for the two markers. The marker frequencies used in the analyses were as previously reported (Seizinger et al., 1988, Bale et al., 1988). A gene frequency of 0.0001 was assumed for the VHL gene. In addition, the program HOMOG (Ott, 1985) was used to test for the existence of heterogeneity in VHL by combining our data with the published RAF1 data.
Von Hippel-Lindau (VHL) disease was initially reported to be linked to the RAF1 oncogene (3~25). We have ascertained and sampled two large multigenerational VEIL families for linkage studies, in order to confirm the localization of the VHL gene as a prelude to fine mapping studies. The probes used in the analysis were ~627 (RAFl) and pHeAl2 (thyroid hormone receptor B) (3~24.1-3~22). VHL was analyzed as an autosomal dominant trait with age-dependent penetrance. The maximum lod score combining both families was z(a) = 2.16 at 8 = 0.0 for RAF1 and z(8) = 2.20 at 8 = 0.05 for thyroid hormone receptor B. Multipoint analysis using the RAF1 and thyroid hormone receptor B loci resulted in a peak lod score of 3.1 conflrming linkage of VHL to this region of chromosome 3. However, the position of VHL relative to the two loci could not be established with certainty. Q 1990
November
Center, Durham, North Carolina 27710
Inc.
Von Hippel-Lindau disorder (VHL) is a rare, autosomal dominant disease characterized by formation of hemangioblastomas in the retina, CNS, and viscera including the kidneys, adrenals, and pancreas. In addition, an increased frequency of pheochromocytoma, renal cell carcinoma, and hypernephromas is associated with the disorder. Age of onset is variable, but development of symptoms is usually in early adulthood (Huson et al., 1986). Seizinger et al. (1988) reported linkage of VHL to RAFl, an oncogene mapping to chromosome 3~25 (Banner et al., 1989), with z(e) = 4.38 at 8 = 0.11. The present report confirms the linkage of VHL to the region of the RAF1 oncogene, inclusive of the thyroid hormone receptor B gene (THRB), located on chromosome 3~24.1-3~22 (McAlpine et al., 1989). Thirty-five individuals from two large VHL families were obtained through Duke University Medical Center and blood was obtained for DNA storage and creation of permanent lymphoblastoma cell lines. Of those 565
All
Copyright 0 1990 rights of reproduction
0&3&%7543/SO $3.00 by Academic Press, Inc. in any form reserved.
566
SHORT
COMMUNICATION
In order to maximize the information available in each pedigree, and potentially gain information on marker order, multipoint analysis using the LINKMAP subprogram of the LINKAGE package was employed. Both the RAF1 and THRB loci were used in the analyses. THRB was fixed at a map distance of 0.13 Morgans from RAF1 (Jonathan Haines, personal communication); Kosambi’s mapping function was used to explain the differences between genetic distance and recombination (Lathrop et al., 1984). VHL was moved sequentially through all positions of the map and the corresponding likelihood was calculated. Multipoint lod scores, i.e., log,, (likelihood difference) of VHL being unlinked versus VHL lying at various positions on the map, were obtained (Keats and Ott, 1989). Results of the two-point analysis showed that family DUK 771 was uninformative for RAFl. Therefore, although a subsection of this family had been previously examined by Seizinger et al. (1988), the family was not contributory to the overall lod score obtained from RAF1 in their analysis and thus could be incorporated into the present analysis. The maximum lod scores combining both families in the two-point analysis were z(e) = 2.16 at 4 = 0.0 for RAF1 and z(& = 2.20 at 8 = 0.05 for THRB. Combining our RAF1 data with those of Seizinger et at. and using the HOMOG computer program gave no evidence for genetic heterogeneity in VHL. The maximum likelihood estimate of y, the proportion of linked families, was 1.0 with a lower 95% confidence limit of 0.8. The results of the multipoint analysis are shown in Fig. 1. A peak lod score of 3.1 was found when VHL was placed at 0.0 recombination with the RAF1 locus. The position of VHL relative to the two loci could not be established with certainty, as the odds favoring this position are only 3:l over a position distal to THRB. In summary, we confirm the linkage of VHL to RAF1 initially reported by Seizinger et al. (1988) and additionally report linkage of VHL to THRB. This supports the location of the VHL gene to the 3p22-pter region, as was found in the Seizinger et al. study. Clinically, VHL appears to demonstrate variable expressivity but there is no evidence at this time to suggest clinical heterogeneity. Heterogeneity analysis of the pooled linkage data supports this hypothesis. The region of 3p continues to be an intriguing area containing multiple loci which appear associated with several oncogene entities including renal cell (Cohen et al., 1984) and small cell carcinoma (Johnson et al., 1988). Because of the extensive periodic radiographic and clinical screening needed to evaluate at-risk individuals for VHL, DNA probes for accurate carrier detection would be a great benefit to family members. We continue work on developing further probes in this region to flank the VHL gene.
4 i 3-
2
2-
8 5
l-
TnAB\\ 0-l
RAF't
FIG. 1. Results of the multipoint analysis RAF1 and THRB. Kosambi’s mapping function recombination fractions into map distances.
between VHL and was used to convert
ACKNOWLEDGMENTS The authors thank Nigel Walker, Fiona Francis, John Pufky, Kenneth Wilkinson, Edward Hanson, and Guillermo Arana for their excellent technical contributions to this work; Peggy Pate and Helen Harbett for data processing; Carol Haynes and Marcy Speer for computer expertise, and Carolyn Turner for manuscript preparation. THRB was kindly provided by C. Weinberger; RAF1 was obtained from the ATCC. This project was supported in part by NIH Grant NS26630, the Leadership and Excellence in Alxheimer’s Disease (LEAD) Award AG07992, and CIDA Grant NS01289.
REFERENCES 1. BALE, A. E., USALA, S., WEINBERGER, AND MCBRIDE, the hc-(ERBA) RFLP. Nucleic 2.
C., WEINTRAUB, B. D., 0. W. (1988). A cDNA probe (Phe Al2) from gene on chromosome 3 detects a high frequency Acids Res. 16: 7756-7756.
BONNER, T., O’BRIEN, S. J., NASH, W. G., RAPP, U. R., MORTON, C. C., AND LIZDER, P. (1989). The human homologs of the raf (mil) oncogene are located on human chromosome 3 and 4. Scknce233:71-74.
3.
COHEN, A. J., LI, F. P., BERG, S., MARCHETTO, D. J., TSAI, S., JACOBS, S. C., AND BROWN, R. S. (1994). Hereditary renal cell carcinoma associated with a chromosomal translocation. N. Engl, J. Med. 301: 592-595.
4.
CONNEXLLY, P. M., EDWARDS, J. H., KIDD, K.-K., LALOUELJ.-M., MORTON, N. E., OTT, J., AND WHITE, R. (1985). Report of the committee on methods of linkage analysis and reporting. Cytogenet. Cell Genet. 40: 356-359.
5.
Go, R. C. P., LAMIELL, J. M., HSIA, Y. E., YUEN, J. W. M., AND PALK, Y. (19&t). Segregation and linkage analysis of von Hippel-Lindau Disease among 220 descendants from one kindred. Amer. J. Hum. Genet. 36: 131-142.
SHORT
COMMUNICATION
6. HAYNES, C. S., PIWXK-VANCE, M. A., HUNG, W-Y., DEu’lXCH, D. B., AND ROSES, A. D. (1988). PEDIGENE-A computerized data collection and enalydr system for genetic laboratories. Amer. J. Hum. Gent%. 43: A146. I. HUSON, S. M., HARPER, P. S., HOIJRIHAN, M. D., COLE, G., WEEKS, R. D., AND COMPSMN, D. A. S. (1986). Cerebellar heemangioblestoma and von Hippel-Lindeu Disease. Brain 109: 1297-1310. 8. JOHNSON, B. E., SAKAGUCHI, A. Y., GAZDAE, A. F., MINNA, J. D., BURCH, D., MARSHALL, A., AND NAYIX% S. L. (1968). Restriction fragment length polymorphism studies show consistent loss of chromosome 3p alleles in smell cell lung cancer patients tumors. J. Clin. Znuest. 82: 502-507. 9. KEATS, B., AND OTT, J. (1989). Report of the committee on linkage and gene order. Cytogenet. Cell Genet. 51: 459-502. 10. LATHROP, G. M., LALOUEL, J. M., JULIER, C., AND OTT, J. (1984). Strategies for multilocus linkage analysis in humans. Proc. Natl. Acad. Sci. USA 81: 3443-3446. 11. MCALPINE, P. J., SHOWS, T. B., BOUCHEIX, C., STRANC, L. C., BEVENT, T. G., PAKSTIS, A. J., AND DO~TE, R. c. (1989). Report of the Nomenclature Committee and the 1989 Catalog of Mapped Genes. Cytogenet. Cell Genet. 51: 13-66. 12. MELMON, K. L., AND ROSEN, S. W. (1964). Lindau’s disease: Review of the literature and study of a large kindred. Amer. J. Med. 36: 595-617.
567
13. m, J. (1985). “Analysis of Human Genetic Linkage” pp. 105119. Johns Hopkins University Press, Baltimore. 14. PERICAK-VANCE, M. A., HUNG, W. Y., YAMAOKA, L., HAYNES, C., BARTLETT, R. J., VANCE, J. M., LEE, J., SIDDIQUE, T., GASKELL, P. C., STAJICH, J., AND ROSES, A. D. (1988s). Systematic gene mapping in man: Date management considerations. Awt. Paedintr. J. Sup& 87-69. 15. PEFUCAK-VANCE,M. A., YAMAOKA, L. H., HAYNES, C. S., SPEER, M. C., HAINES, J. L., GASKELL, P. C., HUNG, W. Y., CLARK, C. M., HEYMAN, A. L., TF~OFATTER, J. A., EISENMENGER, J. P., GILBERT, J. R., LEE, J. E., ALBERTS, M. J., DAWSON, D. V., BARTLETT, R. J., EARL, N. L., SIDDIQUE, T., VANCE, J. M., CONNEALLY, P. M., AND ROSES, A. D. (1988b). Genetic linkage studies in Alzheimer’s Disease families. Erp Neural. 102: 271279. 16. SEIZINGER, B. R., ROULEAU, G. A., OZELJXJS,L. J., LANE, A. H., FARMER, G. E., LAMIELL, J. M., HAINES, J., YUEN, J. W. M., COLLINS, D., MAJOOR-KRAKAUER, D., BONNER, T., MATHEW, C., RUBENSTEIN, A., HALPERIN, J., MCCONKIE-ROSELL, A., GREEN, J. S., TROFATTER, J. A., PONDER, B. A., EIERMAN, L., BOWMER, M. I., AND SCHIMKE, R. (1988). Von Hippel-Lindeu disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature (London) 332: 266-269. 17. WEINBERGER, C., THOMPSON, C. C., ONG, E. S., LEBO, R., GRUOL, D. J., AND EVANS, R. M. (1986). The c-erb-A gene encodes a thyroid hormone receptor. Nature (London) 324: 641644.
