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Membrane-Spanning 4-Domains Subfamily A, MS4A Cluster

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Genetic Variants in Alzheimer's Disease

Abstract

Several genome-wide association studies conducted in the context of Alzheimer’s disease have implicated the association of MS4A variants in disease. The SNPs highlighted in these studies fall within a large LD block and indicate the potential involvement of four genes: MS4A2, MS4A6A, MS4A4E and MS4A4A.

A description of structure, function and regulation is currently lacking for MS4A6A, MS4A4E and MS4A4A proteins. However, the conservation in protein structure and discrete genomic location implies shared structure function relationships with the more experimentally defined MS4A1 and MS4A2. Both MS4A1 and MS4A2 are reported to form and function as part of immunoglobulin receptor signalling complexes involved in calcium signalling. As such, the other MS4A proteins are anticipated to participate in calcium signalling, perhaps as part of a larger signalosome. The evidence of multiple isoforms and the ability of alternative transcripts to moderate the functions of these proteins indicate additional layers of functional complexity. Mutations may have impact on protein structure, protein expression or the relative amounts of isoforms expressed, though this has yet to be fully elucidated.

With the exception of MS4S4E, expression of these candidate proteins has been observed in brain tissue and in cell types associated with immunity and neuroinflammation.

It is not currently possible to specifically define a role for the candidate MS4A proteins in AD. However, it is clear that a disruption in the signalling of the cell types known to express them could contribute to the disease associated immune and neuroinflammatory processes which are well documented.

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Authors and Affiliations

  1. Human Genetics, School of Molecular Medical Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK

    Kristelle Brown, James Turton & Kevin Morgan

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  1. Kristelle Brown
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  2. James Turton
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  3. Kevin Morgan
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Correspondence to Kristelle Brown .

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  1. Queen's Medical Centre, School of Molecular Medical Sciences, University of Nottingham, Hucknall Road, Nottingham, NG7 2UH, United Kingdom

    Kevin Morgan

  2. , Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, 32224, USA

    Minerva M. Carrasquillo

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Brown, K., Turton, J., Morgan, K. (2013). Membrane-Spanning 4-Domains Subfamily A, MS4A Cluster. In: Morgan, K., Carrasquillo, M. (eds) Genetic Variants in Alzheimer's Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7309-1_8

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