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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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          Abstract

          Background

          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.

          Methods

          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.

          Results

          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.

          Conclusion

          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 references38

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          Biology of the adenomatous polyposis coli tumor suppressor.

          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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            Synaptic Wnt signaling—a contributor to major psychiatric disorders?

            Wnt signaling is a key pathway that helps organize development of the nervous system. It influences cell proliferation, cell fate, and cell migration in the developing nervous system, as well as axon guidance, dendrite development, and synapse formation. Given this wide range of roles, dysregulation of Wnt signaling could have any number of deleterious effects on neural development and thereby contribute in many different ways to the pathogenesis of neurodevelopmental disorders. Some major psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders, are coming to be understood as subtle dysregulations of nervous system development, particularly of synapse formation and maintenance. This review will therefore touch on the importance of Wnt signaling to neurodevelopment generally, while focusing on accumulating evidence for a synaptic role of Wnt signaling. These observations will be discussed in the context of current understanding of the neurodevelopmental bases of major psychiatric diseases, spotlighting schizophrenia, bipolar disorder, and autism spectrum disorder. In short, this review will focus on the potential role of synapse formation and maintenance in major psychiatric disorders and summarize evidence that defective Wnt signaling could contribute to their pathogenesis via effects on these late neural differentiation processes.
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              The ABC of APC

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                Author and article information

                Contributors
                marcia.cruz1@upr.edu
                Journal
                Hered Cancer Clin Pract
                Hered Cancer Clin Pract
                Hereditary Cancer in Clinical Practice
                BioMed Central (London )
                1731-2302
                1897-4287
                24 February 2020
                24 February 2020
                2020
                : 18
                : 4
                Affiliations
                [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
                Author information
                http://orcid.org/0000-0001-8147-7457
                Article
                135
                10.1186/s13053-020-0135-3
                7041079
                73650948-6ee5-4feb-8fb6-1b6df05392aa
                © The Author(s). 2020

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), 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 ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 4 December 2019
                : 26 January 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: CA096297/CA096300
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006545, National Institute on Minority Health and Health Disparities;
                Award ID: 2U54MD007587
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                familial adenomatous polyposis,neurocognition,hispanics,fap
                Oncology & Radiotherapy
                familial adenomatous polyposis, neurocognition, hispanics, fap

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