Abstract
The identification of germline mutations in a large number of clinically well-characterised patients with familial adenomatous polyposis (FAP) has allowed the unravelling of several genotype-phenotype relationships that can now be interpreted in the light of the structure and functional domains of the adenomatous polyposis coli (APC) protein. An attenuated phenotype has been found to be associated with mutations at the 5′ end of the gene, while a severe clinical expression was found in patients with the most common mutation at codon 1309. So far, only few mutations in the 3′ half of the gene have been published. We report on two families with a rather mild phenotype due to a frameshift mutation at codon 1597. These families may represent a clue for defining a 5′ border for the occurrence of a second region of attenuated FAP that is localised in the 3′ part of the APC gene. We propose a model to explain the relationship between the severity of the disease and the size of the mutant APC protein.
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Bodmer WF, Bailey CJ, Bodmer J, Bussey HJR, Ellis A, Gorman P, Lucibello FC, Murday VA, Rider SH, Scambler P, Sheer D, Solomon E, Spurr NK (1987) Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 328: 614–616
Caspari R, Friedl W, Mandl M, Möslein G, Kadmon M, Knapp M, Jacobasch K-H, Ecker K-W, Kreißler-Haag D, Timmermanns G, Propping P (1994) Familial adenomatous polyposis: mutation at codon 1309 and early onset of colon cancer. Lancet 343 629–632
Caspari R, Olschwang S, Friedl W, Mandl M, Boisson C, Böker T, Augustin A, Kadmon M, Möslein G, Thomas G, Propping P (1995) Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444. Hum Mol Genet 4:337–340
Evans DGR, Guy SP, Thakker N, Armstrong JG, Dodd C, Davies DR, Babbs C, Clancy T, Warnes T, Sloan P, Taylor TV, Harris R (1993) Non-penetrance and late appearance of polyps in families with familial adenomatous polyposis. Gut 43:1389–1393
Gayther SA, Wells D, SenGupta SB, Chapman P, Neale K, Tsioupra K, Delhanty JDA (1994) Regionally clustered APC mutations are associated with severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli. Hum Mol Genet 3:53–56
Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen 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 characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600
Hodgson SV, Fagg NLK, Talbot IC, Wilkonson M (1994) Deletions of the entire APC gene are associated with sessile colonic polyps. J Med Genet 31:426
Joslyn G, Richardson DS, White R, Albert T (1993) Dimer formation by an N-terminal coiled coil in the APC protein. Proc Natl Acad Sci USA 90:11109–11113
Kinzler KW, Nilbert NC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P, McKechnie D, Finniear R, Markham A, Groffen J, Boguski MS, Altschul SF, Horii A, Ando H, Miyoshi Y, Miki Y, Nishisho I, Nakamura Y (1991) Identification of FAP locus genes from chromosome 5g21. Science 253:661–665
Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823
Laird PW, Jackson-Grusby L, Fazeli A, Dickinson SL, Jung WE, Li En, Weinberg RA, Jaenisch R (1995) Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81:197–205
Levy DB, Smith KJ, Beazer-Barclay Y, Hamilton SR, Vogelstein B, Kinzler KW (1994) Inactivation of both APC alleles in human and mouse tumors. Cancer Res 54:5953–5958
Luongo C, Moser AR, Gledhill S, Dove WF (1994) Loss of APC+ in intestinal adenomas from Min mice. Cancer Res 54:5947–5952
MacPhee M, Chepenik KP, Liddell RA, Nelson KK, Siracusa LD, Buchberg AM (1995) The secretory phospholipase A2 gene is a candidate for the Moral locus, a major modifier of APCMin-induced intestinal neoplasia. Cell 81:957–966
Mandl M, Paffenholz R, Friedl W, Caspari R, Sengteller M, Propping P (1994) Frequency of common and novel inactivating APC mutations in 202 families with familial adenomatous polyposis. Hum Mol Genet 3:181–184
Mandl M, Caspari R, Jauch A, Böker T, Raschke H, Sengteller M, Propping P, Friedl W (1996) Familial adenomatous polyposis: a submicroscopic deletion at the APC locus in a family with mentally normal patients. Hum Genet 97:204–208
Miyaki M, Konishi M, Kikuchi-Yanoshita R, Enomoto M, Igari T, Tanaka K, Muraoka M, Takahashi H, Amada Y, Fukayama M, Maeda Y, Iwama T, Mishima Y, Mori T, Koike M (1994) Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res 54:3011–3020
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
Munemitsu S, Souza B, Müller O, Albert I, Rubinfeld B, Polakis P (1994) The APC gene product associates with microtubules in vivo and promotes their assembly in vitro. Cancer Res 54:3676–3681
Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P (1995) Regulation of intracellular beta-catenin levels by the adenomatons polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci USA 92:3046–3050
Nagase H, Nakamura Y (1993) Mutations of the APC (adenomatous polyposis coli) gene. Hum Mutat 2:425–434
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 52:4055–4057
Olschwang S, Tiret A, Laurent-Puig P, Muleris M, Parc R, Thomas G (1993) Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients. Cell 75:959–968
Oshima M, Oshima H, Kitagawa K, Kobayashi M, Itakura C, Taketo M (1995 a) Loss of APC heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated APC gene. Proc Natl Acad Sci USA 92:4482–4486
Oshima M, Oshima H, Kobayashi M, Tsutsumi M, Taketo MM (1995b) Evidence against dominant negative mechanisms of intestinal polyp formation by APC gene mutations. Cancer Res 55:2719–2722
Paffenholz R, Mandl M, Caspari R, Sengteller M, Propping P, Friedl W (1994) Eleven novel germline mutations in the adenomatous polyposis coli (APC) gene. Hum Mol Genet 3: 1703–1704
Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, Vogelstein B, Kinzler KW (1992) APC mutations occur early during colorectal tumorigenesis. Nature 359 235–237
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
Scott RJ, Luijt R van der, Spycher M, Mary J-L, Müller A, Hoppeler T, Haner M, Müller HJ, Martinoli S, Brazzola P-L, Meera Khan P (1995) Novel germline APC mutation in a large familial adenomatous polyposis kindred displaying variable phenotypes. Gut 36:731–736
Smith KJ, Levy DB, Maupin P, Pollard TD, Vogelstein B, Kinzler KW (1994) Wild-type but not mutant APC associates with the microtubule cytoskeleton. Cancer Res 54:3672:3675
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 LK, 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 LK, Vogelstein B, Kinzler KW (1993b) Association of the APC tumor suppressor protein with catenins. Science 262:1734–1737
Su LK, Burrell M, Hill DE, Gyuris J, Brent R, Wiltshire R, Trent J, Vogelstein B, Kinzler KW (1995) APC binds to the novel protein EB1. Cancer Res 55: 2972–2977
Varesco L, Gismondo V, Presciuttini S, Groden J, Spirio L, Sala P, Rossetti C, De Benedetti L, Bafico A, Heouaine A, Grammatico P, Del Porto G, White R, Bertario L, Ferrara GB (1994) Mutation in a splice-donor site of the APC gene in a family with polyposis and late age of colonic cancer death. Hum Genet 93 281–286
Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9:138–141
Wallis YL, Macdonald F, Hulten M, Morton JEV, McKeown CM, Neoptolemos JP, Keighley M, Morton DG (1994) Genotypephenotype correlation between position of constitutional APC gene mutation and CHRPE expression in familial adenomatous polyposis. Hum Genet 94:543–548
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Friedl, W., Meuschel, S., Lamberti, C. et al. Attenuated familial adenomatous polyposis due to a mutation in the 3′ part of the APC gene. A clue for understanding the function of the APC protein. Hum Genet 97, 579–584 (1996). https://doi.org/10.1007/BF02281864
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DOI: https://doi.org/10.1007/BF02281864