The MUC6/AP2A2 locus and its relevance to Alzheimer's disease: A review

Peter T. Nelson; David W. Fardo; Yuriko Katsumata

doi:10.1093/JNEN/NLAA024

The MUC6/AP2A2 locus and its relevance to Alzheimer's disease: A review

Peter T. Nelson, David W. Fardo, Yuriko Katsumata

Research output: Contribution to journal › Review article › peer-review

11 Scopus citations

Abstract

We recently reported evidence of Alzheimer's disease (AD)- linked genetic variation within the mucin 6 (MUC6) gene on chromosome 11p, nearby the adaptor-related protein complex 2 subunit alpha 2 (AP2A2) gene. This locus has interesting features related to human genomics and clinical research. MUC6 gene variants have been reported to potentially influence viral - including herpesvirus - immunity and the gut microbiome. Within the MUC6 gene is a unique variable number of tandem repeat (VNTR) region. We discovered an association between MUC6 VNTR repeat expansion and AD pathologic severity, particularly tau proteinopathy. Here, we review the relevant literature. The AD-linked VNTR polymorphism may also influence AP2A2 gene expression. AP2A2 encodes a polypeptide component of the adaptor protein complex, AP-2, which is involved in clathrin-coated vesicle function and was previously implicated in AD pathogenesis. To provide background information, we describe some key knowledge gaps in AD genetics research. The "missing/hidden heritability problem"of AD is highlighted. Extensive portions of the human genome, including the MUC6 VNTR, have not been thoroughly evaluated due to limitations of existing high-throughput sequencing technology. We present and discuss additional data, along with cautionary considerations, relevant to the hypothesis that MUC6 repeat expansion influences AD pathogenesis.

Original language	English
Pages (from-to)	568-584
Number of pages	17
Journal	Journal of Neuropathology and Experimental Neurology
Volume	79
Issue number	6
DOIs	https://doi.org/10.1093/JNEN/NLAA024
State	Published - 2021

Bibliographical note

Funding Information:
From the Sanders-Brown Center on Aging (PTN, DWF, YK); Department of Pathology (PTN); and Department of Biostatistics (DWF, YK), Univer-sity of Kentucky, Lexington, Kentucky Send correspondence to: Peter T. Nelson, MD, PhD, Rm 311 Sanders-Brown Center on Aging, 800 S. Limestone Avenue, Lexington, KY 40536; E-mail: peter.nelson@uky.edu Funding included grants P30 AG028383, R01 AG057187, R01 AG042475, R56 AG057191, and U01 AG016976 from the National Institute on Aging/National Institutes of Health (NIH). The Genotype-Tissue Expres-sion (GTEx) project was supported by the Common Fund of the Office of the Director of the NIH, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. We are deeply grateful to all of the study participants, clini-cal workers, and researchers who helped make this article possible. See Supplementary Data for additional acknowledgments.

Publisher Copyright:
© 2020 American Association of Neuropathologists, Inc.

Keywords

APOE
Alzheimer's Disease Sequencing Project (ADSP)
Amyloid
Copy number variation (CNV)
Endocytosis
Genome-wide association study (GWAS)
Whole-exome sequencing (WES)

ASJC Scopus subject areas

Pathology and Forensic Medicine
Neurology
Clinical Neurology
Cellular and Molecular Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/JNEN/NLAA024

Cite this

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title = "The MUC6/AP2A2 locus and its relevance to Alzheimer's disease: A review",

abstract = "We recently reported evidence of Alzheimer's disease (AD)- linked genetic variation within the mucin 6 (MUC6) gene on chromosome 11p, nearby the adaptor-related protein complex 2 subunit alpha 2 (AP2A2) gene. This locus has interesting features related to human genomics and clinical research. MUC6 gene variants have been reported to potentially influence viral - including herpesvirus - immunity and the gut microbiome. Within the MUC6 gene is a unique variable number of tandem repeat (VNTR) region. We discovered an association between MUC6 VNTR repeat expansion and AD pathologic severity, particularly tau proteinopathy. Here, we review the relevant literature. The AD-linked VNTR polymorphism may also influence AP2A2 gene expression. AP2A2 encodes a polypeptide component of the adaptor protein complex, AP-2, which is involved in clathrin-coated vesicle function and was previously implicated in AD pathogenesis. To provide background information, we describe some key knowledge gaps in AD genetics research. The {"}missing/hidden heritability problem{"}of AD is highlighted. Extensive portions of the human genome, including the MUC6 VNTR, have not been thoroughly evaluated due to limitations of existing high-throughput sequencing technology. We present and discuss additional data, along with cautionary considerations, relevant to the hypothesis that MUC6 repeat expansion influences AD pathogenesis.",

keywords = "APOE, Alzheimer's Disease Sequencing Project (ADSP), Amyloid, Copy number variation (CNV), Endocytosis, Genome-wide association study (GWAS), Whole-exome sequencing (WES)",

author = "Nelson, {Peter T.} and Fardo, {David W.} and Yuriko Katsumata",

note = "Funding Information: From the Sanders-Brown Center on Aging (PTN, DWF, YK); Department of Pathology (PTN); and Department of Biostatistics (DWF, YK), Univer-sity of Kentucky, Lexington, Kentucky Send correspondence to: Peter T. Nelson, MD, PhD, Rm 311 Sanders-Brown Center on Aging, 800 S. Limestone Avenue, Lexington, KY 40536; E-mail: peter.nelson@uky.edu Funding included grants P30 AG028383, R01 AG057187, R01 AG042475, R56 AG057191, and U01 AG016976 from the National Institute on Aging/National Institutes of Health (NIH). The Genotype-Tissue Expres-sion (GTEx) project was supported by the Common Fund of the Office of the Director of the NIH, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. We are deeply grateful to all of the study participants, clini-cal workers, and researchers who helped make this article possible. See Supplementary Data for additional acknowledgments. Publisher Copyright: {\textcopyright} 2020 American Association of Neuropathologists, Inc.",

year = "2021",

doi = "10.1093/JNEN/NLAA024",

language = "English",

volume = "79",

pages = "568--584",

number = "6",

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TY - JOUR

T1 - The MUC6/AP2A2 locus and its relevance to Alzheimer's disease

T2 - A review

AU - Nelson, Peter T.

AU - Fardo, David W.

AU - Katsumata, Yuriko

N1 - Funding Information: From the Sanders-Brown Center on Aging (PTN, DWF, YK); Department of Pathology (PTN); and Department of Biostatistics (DWF, YK), Univer-sity of Kentucky, Lexington, Kentucky Send correspondence to: Peter T. Nelson, MD, PhD, Rm 311 Sanders-Brown Center on Aging, 800 S. Limestone Avenue, Lexington, KY 40536; E-mail: peter.nelson@uky.edu Funding included grants P30 AG028383, R01 AG057187, R01 AG042475, R56 AG057191, and U01 AG016976 from the National Institute on Aging/National Institutes of Health (NIH). The Genotype-Tissue Expres-sion (GTEx) project was supported by the Common Fund of the Office of the Director of the NIH, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. We are deeply grateful to all of the study participants, clini-cal workers, and researchers who helped make this article possible. See Supplementary Data for additional acknowledgments. Publisher Copyright: © 2020 American Association of Neuropathologists, Inc.

PY - 2021

Y1 - 2021

N2 - We recently reported evidence of Alzheimer's disease (AD)- linked genetic variation within the mucin 6 (MUC6) gene on chromosome 11p, nearby the adaptor-related protein complex 2 subunit alpha 2 (AP2A2) gene. This locus has interesting features related to human genomics and clinical research. MUC6 gene variants have been reported to potentially influence viral - including herpesvirus - immunity and the gut microbiome. Within the MUC6 gene is a unique variable number of tandem repeat (VNTR) region. We discovered an association between MUC6 VNTR repeat expansion and AD pathologic severity, particularly tau proteinopathy. Here, we review the relevant literature. The AD-linked VNTR polymorphism may also influence AP2A2 gene expression. AP2A2 encodes a polypeptide component of the adaptor protein complex, AP-2, which is involved in clathrin-coated vesicle function and was previously implicated in AD pathogenesis. To provide background information, we describe some key knowledge gaps in AD genetics research. The "missing/hidden heritability problem"of AD is highlighted. Extensive portions of the human genome, including the MUC6 VNTR, have not been thoroughly evaluated due to limitations of existing high-throughput sequencing technology. We present and discuss additional data, along with cautionary considerations, relevant to the hypothesis that MUC6 repeat expansion influences AD pathogenesis.

AB - We recently reported evidence of Alzheimer's disease (AD)- linked genetic variation within the mucin 6 (MUC6) gene on chromosome 11p, nearby the adaptor-related protein complex 2 subunit alpha 2 (AP2A2) gene. This locus has interesting features related to human genomics and clinical research. MUC6 gene variants have been reported to potentially influence viral - including herpesvirus - immunity and the gut microbiome. Within the MUC6 gene is a unique variable number of tandem repeat (VNTR) region. We discovered an association between MUC6 VNTR repeat expansion and AD pathologic severity, particularly tau proteinopathy. Here, we review the relevant literature. The AD-linked VNTR polymorphism may also influence AP2A2 gene expression. AP2A2 encodes a polypeptide component of the adaptor protein complex, AP-2, which is involved in clathrin-coated vesicle function and was previously implicated in AD pathogenesis. To provide background information, we describe some key knowledge gaps in AD genetics research. The "missing/hidden heritability problem"of AD is highlighted. Extensive portions of the human genome, including the MUC6 VNTR, have not been thoroughly evaluated due to limitations of existing high-throughput sequencing technology. We present and discuss additional data, along with cautionary considerations, relevant to the hypothesis that MUC6 repeat expansion influences AD pathogenesis.

KW - APOE

KW - Alzheimer's Disease Sequencing Project (ADSP)

KW - Amyloid

KW - Copy number variation (CNV)

KW - Endocytosis

KW - Genome-wide association study (GWAS)

KW - Whole-exome sequencing (WES)

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U2 - 10.1093/JNEN/NLAA024

DO - 10.1093/JNEN/NLAA024

M3 - Review article

C2 - 32357373

AN - SCOPUS:85085156708

VL - 79

SP - 568

EP - 584

IS - 6

ER -

The MUC6/AP2A2 locus and its relevance to Alzheimer's disease: A review

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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