Abstract
Mutations in the adenomatous polyposis coli (APC) gene are responsible for the disease familial adenomatous polyposis (FAP), a dominantly inherited predispostion to colorectal cancer. The most common extra-colonic manifestation is congenital hypertrophy of the retinal pigment epithelium (CHRPE), expressed in up to 90% of FAP kindreds. Chain-terminating APC mutations were characterised in 26 unrelated FAP patients. Results show that CHRPE expression is determined by the length of truncated protein product. CHRPE is therefore the first extracolonic manifestation of FAP to be shown to be under the control of the APC mutation site and should facilitate the detection of constitutional APC mutations in FAP kindreds.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baker RH, Heinemann MH, Miller HH, Decosse JJ (1988) Hyperpigmented lesions of the retinal pigment epithelium in familial adenomatous polyposis. Am J Med Genet 31:427–435
Berk T, Cohen Z, McLeod RS, Parker JA (1988) Congenital hypertrophy of the retinal pigment epithelium as a marker for familial adenomatous polyposis. Dis Colon Rectum 31:253–257
Blair NP, Trempe CL (1980) Hypertrophy of the retinal pigment epithelium associated with Gardner's syndrome. Am J Ophthalmol 90:661–667
Bülow S (1991) Diagnosis of familial adenomatous polyposis. World J Surg 15:41–46
Burn J, Chapman P, Delhanty J, Wood C, Lalloo F, Cachon-Gonzalez MB, Tsioupra K, Church W, Rhodes M, Gunn A (1991) The UK Northern Region genetics register for familial adenomatous polyposis: the use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk assessment. J Med Genet 28:289–296
Bussey HJR (1975) Familial polyposis coli: family studies, histopathology, differential diagnosis and results of treatment. Johns Hopkins University Press, Baltimore
Caspari R, Friedl W, Mandl M, Moslein G, Kadmon M, Knapp M (1994) Familial adenomatous polyposis: mutation at codon 1309 and early onset of colon cancer. Lancet 343:629–632
Cross I, Delhanty J, Chapman P, Bowles LV, Griffen D, Wolstenholme J, Bradburn M, Brown J, Wood C, Gunn A, Burn J (1992) An intrachromosomal insertion causing 5q22 deletion and familial adenomatous polyposis coli in two generations. J Med Genet 29:175–179
Fodde R, Luijt R van der, Wijnen J, Tops C, Klift H van der, Leeuwen-Cornelisse I van, Griffioen G, Vasen H, Khan PM (1992) Eight novel inactivating germ line mutations at the APC gene identified by denaturing gradient gel electrophoresis. Genomics 13:1162–1168
Gardner EJ (1962) Follow-up study of a family group exhibiting dominant inheritance for a syndrome including intestinal polyps, osteomas, fibromas and epidermoid cysts. Am J Genet 14:376
Gardner EJ, Richards SC (1953) Multiple cutaneous and subcutaneous lesions occuring simultaneously with hereditary polyposis osteomatosis. Am J Hum Genet 5:139–147
Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertson H, Joslyn G, Stevens J, Spirio L, Robertson M, Sargeant L, Krapcho K, Wolff E, Burt R, Hughes JP, Warrington J, McPherson J, Wasmuth J, Le Paslier D, Abderrahim H, Cohen D, Leppert M, White R (1991) Identification and characterisation of the familial adenomatous gene. Cell 66:589–600
Groden J, Gelbert L, Thliveris A, Nelson L, Robertson M, Joslyn G, Samowitz W, Spirio L, Carlson M, Burt R, Leppert M, White R (1993) Mutational analysis of patients with adenomatous polyposis: identical inactivating mutations in unrelated individuals. Am J Hum Genet 52:263–272
Hodgson SV, Coonar AS, Hanson PJV, Cottrell S, Scriven PN, Jones T, Hawley PR, Wilkinson ML (1992) Two cases of 5q deletions in patients with familial adenomatous polyposis: possible link with Caroli's disease. J Med Genet 30:369–375
Iwama T, Mishima Y, Okamoto N, Inoue J (1990) Association of congenital hypertrophy of the retinal pigment epithelium with familial adenomatous polyposis. Br J Surg 77:273–276
Kinzler KW, Nilbert MC, Su L-K, Vogelstein B, Bryan T, Levy D, Smith K, Preisinger A, Hedge P, McKechnie D, Finniear R, Markham A, Groffen J, Boguski M, Altschul S, Horii A, Ando H, Miyoshi Y, Miki Y, Nishisho I, Nakamura Y (1991) Identification of FAP locus genes from chromosome 5q21. Science 253:661–665
Lerman LS, Silverstein K (1987) Computational simulation of DNA melting and its application to denaturing gradient gel electrophoresis. Methods Enzymol 155:482–501
Lewis RA, Crowder WE, Eierman LA, Nussbaum RL, Ferrell RE (1984) The Gardner syndrome: significance of ocular features. Ophthalmology 91:916–925
Li FP, Thurber WA, Seddon J, Holmes GE (1987) Hepatoblastoma in families with polyposis coli. JAMA 257:2475–2477
Lotfi AM, Dozois RR, Gordon H, Hruska LS, Weiland LH, Carryer PW, Hurt RD (1989) Mesenteric fibromatosis complicating familial adenomatous polyposis: predisposing factors and results of treatment. Int J Colorectal Dis 4:30–36
Miyoshi Y, Ando H, Nagase H, Nishisho I, Horii A, Miki Y, Mori T, Utsunomiya J, Baba S, Petersen G, Hamilton SR, Kinzler KW, Vogelstein B, Nakamura Y (1992) Germ line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci USA 89:4452–4456
Morton DG, Gibson J, Macdonald F, Brown R, Haydon J, Cullen R, Rindl M, Hultén M, Neoptolemos JP, Keighley MRB, McKeown CM (1992) Role of congenital hypertrophy of the retinal pigment epithelium in the predictive diagnosis of familial adenomatous polyposis. Br J Surg 79:689–693
Nagase H, Miyoshi Y, Horii A, Aoki T, Ogawa M, Utsunomiya J, Baba S, Sasazuki T, Nakamura Y (1992) Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res 52:4057
Olschwang S, Laurent-Puig P, Groden J, White R, Thomas G (1993 a) Germ-line mutations in the first 14 exons of the adenomatous polyposis coli (APC) gene. Am J Hum Genet 52:272–279
Olschwang S, Tiret A, Laurent-Puig P, Muleris M, Parc R, Thomas G (1993 b) Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis oli patients. Cell 75:959–968
Ozawa M, Rinwald M, Kemler R (1990) Uvomorulin-catenin complex formation is regulated by a specific domain in the cytoplasmic region of the cell adhesion molecule. Proc Natl Acad Sci USA 87:4246–4250
Paul P, Letteboer T, Gelbert L, Groden J, White R, Coppes MJ (1993) Identical APC exon 15 mutations result in a variable phenotype in familial adenomatous polyposis. Hum Mol Genet 2:925–931
Polkingthoren PJ, Ritchie S, Neale K, Schoeppner G, Thompson JP, Jay BS (1990) Pigmented lesions of the retinal pigment epithelium and familial adenomatous polyposis. Eye 4:216–221
Romania A, Zakov N, McGannon E, Schroeder T, Heyen F, Jagelman DG (1989) Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis. Ophthalmology 96:879–884
Rubinfeld B, Souza B, Albert I, Müller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P (1993) Association of the APC gene product with β-catenin. Science 262:1731–1734
Smith KJ, Johnson KA, Bryan TM, Hill DE, Markowitz S, Willson JK, Paraskeva C, Petersen G, Hamilton SR, Vogelstein B, Kinzler KW (1993) The APC gene product in normal and tumour cells. Proc Natl Acad Sci USA 90:2846–2850
Spirio L, Olschwang S, Groden J, Robertson M, Samowitz W, Joslyn G, Gelbert L, Thliveris A, Carlson M, Otterud B, Lynch H, Watson P, Lynch P, Laurent-Puig P, Burt R, Hughes JP, Thomas G, Leppert M, White R (1993) Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75:951–957
Su L-K, Johnson KA, Smith KJ, Hill DE, Vogelstein B, Kinzler KW (1993 a) Association between wild type and mutant APC gene products. Cancer Res 53:2728–2731
Su L-K, Vogelstein B, Kinzler KW (1993 b) Association of the APC tumour suppressor protein with catenins. Science 262:1734–1737
Traboulsi EI, Krush AJ, Gardner EJ, Booker SV, Offerhaus GJ, Yardley JH, Hamilton SR, Luk GD, Giardiello FM, Welsh SB, Hughes JP, Maumenee IH (1987) Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome. N Engl J Med 316:661–667
Varesco L, Gismondi V, James R, Robertson M, Grammatico P, Groden J, Casarino L, De Benedetti L, Bafico A, Bertario L, Sala P, Sassatelli R, Ponz de Leon M, Biasco G, Allegretti A, Aste H, De Sanctis S, Rossetti C, Illeni MT, Sciarra A, Del Porto G, White R, Ferrara GB (1993) Identification of APC gene mutations in Italian adenomatous polyposis coli patients by PCR-SSCP analysis. Am J Hum Genet 52:280–285
Wallis Y, Macdonald F, Morton D, McKeown C, Fodde R, Luijt R Van der, Renault B, Khan PM, Keighley M, Hultén M (1993) Detection of germline mutations in the APC gene in FAP families. J Med Genet 30:333
Wallis Y, Macdonald F, Morton D, McKeown C, Fodde R, Luijt R Van der, Khan PM, Neoptolemos J, Keighley M, Hultén M (1994) Identification of constitutional APC mutations in FAP families. Int J Colorectal Dis (in Press)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wallis, Y.L., Macdonald, F., Hultén, M. et al. Genotype-phenotype correlation between position of constitutional APC gene mutation and CHRPE expression in familial adenomatous polyposis. Hum Genet 94, 543–548 (1994). https://doi.org/10.1007/BF00211023
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00211023