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      Ubiquitous neurocognitive dysfunction in familial adenomatous polyposis: proof-of-concept of the role of APC protein in neurocognitive function

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          Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by germline mutations in the APC gene. Patients with FAP have multiple extraintestinal manifestations that follow a genotype-phenotype pattern; however, few data exist characterizing their cognitive abilities. Given the role of the APC protein in development of the central nervous system, we hypothesized that patients with FAP would show differences in cognitive functioning compared to controls.


          Matched case-control study designed to evaluate cognitive function using the Test of Nonverbal Intelligence-4, the Bateria III Woodcock-Munoz, and the Behavior Rating Inventory of Executive Functions-Adult. Twenty-six individuals with FAP (mean age = 34.2 ± 15.0 years) and 25 age-gender and educational level matched controls (mean age = 32.7 ± 13.8 years) were evaluated.


          FAP-cases had significantly lower IQ ( p = 0.005). Across all tasks of the Batería III Woodcock-Muñoz, FAP-cases performed significantly lower than controls, with all of the summary scores falling in the bottom quartile compared to controls ( p < 0.0001). Patients with FAP scored within the deficient range for Long-Term Retrieval and Cognitive Fluency.


          APC protein has an important role in neurocognitive function. The pervasive nature of the observed cognitive dysfunction suggests that loss or dysfunction of the APC protein impacts processes in cortical and subcortical brain regions. Additional studies examining larger ethnically diverse cohorts with FAP are warranted.

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          Most cited references 40

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          Biology of the adenomatous polyposis coli tumor suppressor.

           K Goss,  J Groden (2000)
          The adenomatous polyposis coli (APC) gene was first identified as the gene mutated in an inherited syndrome of colon cancer predisposition known as familial adenomatous polyposis coli (FAP). Mutation of APC is also found in 80% of all colorectal adenomas and carcinomas and is one of the earliest mutations in colon cancer progression. Similar to other tumor suppressor genes, both APC alleles are inactivated by mutation in colon tumors, resulting in the loss of full-length protein in tumor cells. The functional significance of altering APC is the dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, which include cell cycle progression, migration, differentiation, and apoptosis. Roles for APC in some of these processes are in large part attributable to its ability to regulate cytosolic levels of the signaling molecule beta-catenin and to affect the transcriptional profile in cells. This article summarizes numerous genetic, biochemical, and cell biologic studies on the mechanisms of APC-mediated tumor suppression. Mouse models of FAP, in which the APC gene has been genetically inactivated, have been particularly useful in testing therapeutic and chemopreventive strategies. These data have significant implications for colorectal cancer treatment approaches as well as for understanding other disease genes and cancers of other tissue types.
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            APC and GSK-3beta are involved in mPar3 targeting to the nascent axon and establishment of neuronal polarity.

            In developing hippocampal neurons in culture, the evolutionarily conserved polarity complex mPar3/mPar6/aPKC selectively accumulates at the tip of one, and only one, of the immature neurites of a neuron and thus specifies the axon and generates neuronal polarity. How mPar3/mPar6 is enriched at the tip of the nascent axon, but not the dendrites, is not fully understood. Here, we report that mPar3 forms a complex with adenomatous polyposis coli (APC) and kinesin superfamily (KIF) 3A, proteins that move along microtubules. In polarizing hippocampal neurons, APC selectively accumulates at the nascent axon tip and colocalizes with mPar3. Expression of dominant-negative C terminus deletion mutants of APC or ectopic expression of APC leads to dislocalization of mPar3 and defects in axon specification and neuronal polarity. In addition to spatial polarization of APC, the selective inactivation of the GSK-3beta activity at the nascent axon tip is required for mPar3 targeting and polarization and establishing neuronal polarity. These results suggest that mPar3 is polarized in developing neurons through APC- and kinesin-mediated transport to the plus ends of rapidly growing microtubules at the nascent axon tip, a process that involves a spatially regulated GSK-3beta activity.
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              The adenomatous polyposis coli (APC) tumor suppressor.

               P Polakis (1997)
              Defects in the APC gene are inarguably linked to the progression of colon cancers that arise both sporadically and through the transmission of germline mutations. Genetic evidence from humans and mouse models suggest that APC is a classic tumor suppressor in that both alleles likely require inactivation for tumor growth to ensue. Nearly all of the mutations, germline and somatic, result in premature termination of the single polypeptide chain, normally consisting of 2843 amino acids. Several definable motifs have now been mapped to the linear amino acid sequence of the APC polypeptide. These include an oligomerization domain, armadillo repeats, binding sites for beta-catenin, the human discs large protein, microtubules, and other proteins of unknown function. Inactivation of APC in cancer is likely due to loss of function(s) normally associated with the deleted protein structure.

                Author and article information

                Hered Cancer Clin Pract
                Hered Cancer Clin Pract
                Hereditary Cancer in Clinical Practice
                BioMed Central (London )
                24 February 2020
                24 February 2020
                : 18
                [1 ]ISNI 0000 0004 0462 1680, GRID grid.267033.3, Department of Medicine, , University of Puerto Rico School of Medicine, ; UPR Medical Sciences Campus, PO BOX 365067, San Juan, 00936 Puerto Rico
                [2 ]ISNI 0000 0004 0462 1680, GRID grid.267033.3, Department of Biochemistry, , University of Puerto Rico School of Medicine, ; San Juan, Puerto Rico
                [3 ]ISNI 0000 0004 0462 1680, GRID grid.267033.3, Department of Medicine, Neurology Section, , University of Puerto Rico School of Medicine, ; San Juan, Puerto Rico
                [4 ]ISNI 0000 0004 0462 1680, GRID grid.267033.3, Division of Cancer Biology, , University of Puerto Rico Comprehensive Cancer Center, ; San Juan, Puerto Rico
                [5 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Division of Gastroenterology, School of Medicine, , Johns Hopkins University, ; Baltimore, MD USA
                [6 ]ISNI 0000 0001 0742 0364, GRID grid.168645.8, University of Massachusetts Medical School, ; Worcester, MA USA
                [7 ]ISNI 0000000122483208, GRID grid.10698.36, Department of Allied Health Sciences, School of Medicine, , University of North Carolina-Chapel Hill, ; Chapel Hill, NC USA
                © The Author(s). 2020

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

                Funded by: FundRef, National Cancer Institute;
                Award ID: CA096297/CA096300
                Award Recipient :
                Funded by: FundRef, National Institute on Minority Health and Health Disparities;
                Award ID: 2U54MD007587
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                © The Author(s) 2020

                Oncology & Radiotherapy

                hispanics, familial adenomatous polyposis, neurocognition, fap


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