G2Cdb::Human Disease report

Disease id
D00000111
Name
Familial adenomatous polyposis
Nervous system disease
no

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002235 CTNNB1
catenin (cadherin-associated protein), beta 1, 88kDa
Y (10398435) Microinsertion (MI) N
G00002235 CTNNB1
catenin (cadherin-associated protein), beta 1, 88kDa
Y (10398435) Deletion (D) N
G00002235 CTNNB1
catenin (cadherin-associated protein), beta 1, 88kDa
Y (14691304) No mutation found (N) N

References

  • APC haploinsufficiency, but not CTNNB1 or CDH1 gene mutations, accounts for a fraction of familial adenomatous polyposis patients without APC truncating mutations.

    Venesio T, Balsamo A, Rondo-Spaudo M, Varesco L, Risio M and Ranzani GN

    Unit of Pathology, Institute for Cancer Research and Treatment, Candiolo-Torino, Genova, Italy.

    Familial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by the development of hundreds to thousands of colorectal adenomatous polyps. In addition to the classic form, there is also attenuated polyposis (attenuated adenomatous polyposis coli; AAPC), which is characterized by a milder phenotype. FAP/AAPC is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Very recently, germline mutations in the base-excision repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas in a subset of patients. APC pathogenic alterations are mostly (>95%) represented by frameshift or nonsense mutations leading to the synthesis of a truncated protein. We identified 20 APC truncating mutation carriers out of 30 FAP/AAPC patients from different Italian kindreds. In the remaining 10 patients, we searched for alterations other than truncating mutations by enzymatic mutation detection, real-time quantitative RT-PCR, and genotyping of polymorphic markers encompassing the APC locus. Moreover, to assess whether mutations of genes interacting with APC can substitute or act in association with APC alterations, we sequenced both CTNNB1 (beta-catenin) and CDH1 (E-cadherin) genes. No CTNNB1 or CDH1 mutations were found. On the contrary, four patients showed a reduced APC gene expression compared with healthy subjects. In three of the four cases, genotyping results were compatible with a constitutive allelic deletion. In one case this conclusion was confirmed by haplotype segregation analysis. Our results support the notion that FAP/AAPC can result from APC constitutive haploinsufficiency, with gene deletion being a possible cause of reduced gene expression.

    Laboratory investigation; a journal of technical methods and pathology 2003;83;12;1859-66

  • Germline mutations are frequent in the APC gene but absent in the beta-catenin gene in familial adenomatous polyposis patients.

    Cao X, Eu KW, Seow-Choen F and Cheah PY

    Department of Colorectal Surgery, Singapore General Hospital, Outram Road, Republic of Singapore.

    Inactivation of the adenomatous polyposis coli (APC) gene has been shown to initiate the majority of colorectal cancer (CRC), including a familial form called familial adenomatous polyposis (FAP). One consequence of the APC mutation is the activation of the beta-catenin (CTNNB1)/T-cell transcription factor (Tcf) pathway. A recent study has shown that about half of the sporadic CRC lacking APC mutation has CTNNB1 mutation, suggesting that CTNNB1 mutation can substitute for APC mutation in the initiation of colorectal tumorigenesis. However, the frequency of CTNNB1 germline mutation in FAP has not been reported. In the present study, we investigated the frequencies of APC and CTNNB1 germline mutations in 26 unrelated FAP families. We used the Protein Truncation Test (PTT) to screen the entire coding region of APC and found germline mutations in twenty families. We then screened for CTNNB1 germline mutations in the rest of the families lacking detectable APC mutations. No missense mutations at GSK-3beta phosphorylation sites or interstitial deletion of exon 3 of CTNNB1 was found. Our results indicate that APC germline mutations are frequent but CTNNB1 germline mutations are rare in FAP patients, suggesting that CTNNB1 mutation cannot substitute for APC mutation in the initiation of FAP. Genes Chromosomes Cancer 25:396-398, 1999.

    Genes, chromosomes & cancer 1999;25;4;396-8

Literature (2)

Pubmed - human_disease

  • APC haploinsufficiency, but not CTNNB1 or CDH1 gene mutations, accounts for a fraction of familial adenomatous polyposis patients without APC truncating mutations.

    Venesio T, Balsamo A, Rondo-Spaudo M, Varesco L, Risio M and Ranzani GN

    Unit of Pathology, Institute for Cancer Research and Treatment, Candiolo-Torino, Genova, Italy.

    Familial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by the development of hundreds to thousands of colorectal adenomatous polyps. In addition to the classic form, there is also attenuated polyposis (attenuated adenomatous polyposis coli; AAPC), which is characterized by a milder phenotype. FAP/AAPC is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Very recently, germline mutations in the base-excision repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas in a subset of patients. APC pathogenic alterations are mostly (>95%) represented by frameshift or nonsense mutations leading to the synthesis of a truncated protein. We identified 20 APC truncating mutation carriers out of 30 FAP/AAPC patients from different Italian kindreds. In the remaining 10 patients, we searched for alterations other than truncating mutations by enzymatic mutation detection, real-time quantitative RT-PCR, and genotyping of polymorphic markers encompassing the APC locus. Moreover, to assess whether mutations of genes interacting with APC can substitute or act in association with APC alterations, we sequenced both CTNNB1 (beta-catenin) and CDH1 (E-cadherin) genes. No CTNNB1 or CDH1 mutations were found. On the contrary, four patients showed a reduced APC gene expression compared with healthy subjects. In three of the four cases, genotyping results were compatible with a constitutive allelic deletion. In one case this conclusion was confirmed by haplotype segregation analysis. Our results support the notion that FAP/AAPC can result from APC constitutive haploinsufficiency, with gene deletion being a possible cause of reduced gene expression.

    Laboratory investigation; a journal of technical methods and pathology 2003;83;12;1859-66

  • Germline mutations are frequent in the APC gene but absent in the beta-catenin gene in familial adenomatous polyposis patients.

    Cao X, Eu KW, Seow-Choen F and Cheah PY

    Department of Colorectal Surgery, Singapore General Hospital, Outram Road, Republic of Singapore.

    Inactivation of the adenomatous polyposis coli (APC) gene has been shown to initiate the majority of colorectal cancer (CRC), including a familial form called familial adenomatous polyposis (FAP). One consequence of the APC mutation is the activation of the beta-catenin (CTNNB1)/T-cell transcription factor (Tcf) pathway. A recent study has shown that about half of the sporadic CRC lacking APC mutation has CTNNB1 mutation, suggesting that CTNNB1 mutation can substitute for APC mutation in the initiation of colorectal tumorigenesis. However, the frequency of CTNNB1 germline mutation in FAP has not been reported. In the present study, we investigated the frequencies of APC and CTNNB1 germline mutations in 26 unrelated FAP families. We used the Protein Truncation Test (PTT) to screen the entire coding region of APC and found germline mutations in twenty families. We then screened for CTNNB1 germline mutations in the rest of the families lacking detectable APC mutations. No missense mutations at GSK-3beta phosphorylation sites or interstitial deletion of exon 3 of CTNNB1 was found. Our results indicate that APC germline mutations are frequent but CTNNB1 germline mutations are rare in FAP patients, suggesting that CTNNB1 mutation cannot substitute for APC mutation in the initiation of FAP. Genes Chromosomes Cancer 25:396-398, 1999.

    Genes, chromosomes & cancer 1999;25;4;396-8

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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