Altered GPM6A/M6 Dosage Impairs Cognition and Causes Phenotypes Responsive to Cholesterol in Human and Drosophila
Gregor A, Kramer JM, Van Der Voet M, Schanze I, Uebe S, Donders R, Reis A, Schenck A, Zweier C (2014)
Publication Type: Journal article
Publication year: 2014
Journal
Book Volume: 35
Pages Range: 1495-505
Journal Issue: 12
DOI: 10.1002/humu.22697
Abstract
Glycoprotein M6A (GPM6A) is a neuronal transmembrane protein of the PLP/DM20 (proteolipid protein) family that associates with cholesterol-rich lipid rafts and promotes filopodia formation. We identified a de novo duplication of the GPM6A gene in a patient with learning disability and behavioral anomalies. Expression analysis in blood lymphocytes showed increased GPM6A levels. An increase of patient-derived lymphoblastoid cells carrying membrane protrusions supports a functional effect of this duplication. To study the consequences of GPM6A dosage alterations in an intact nervous system, we employed Drosophila melanogaster as a model organism. We found that knockdown of Drosophila M6, the sole member of the PLP family in flies, in the wing, and whole organism causes malformation and lethality, respectively. These phenotypes as well as the protrusions of patient-derived lymphoblastoid cells with increased GPM6A levels can be alleviated by cholesterol supplementation. Notably, overexpression as well as loss of M6 in neurons specifically compromises long-term memory in the courtship conditioning paradigm. Our findings thus indicate a critical role of correct GPM6A/M6 levels for cognitive function and support a role of the GPM6A duplication for the patient's phenotype. Together with other recent findings, this study highlights compromised cholesterol homeostasis as a recurrent feature in cognitive phenotypes.
Authors with CRIS profile
Anne Gregor
Lehrstuhl für Humangenetik
Steffen Uebe
Institute of Human Genetics
André Wiesmann da Silva Reis
Lehrstuhl für Humangenetik
Christiane Zweier
Lehrstuhl für Humangenetik
Involved external institutions
Netherlands (NL)How to cite
APA:
Gregor, A., Kramer, J.M., Van Der Voet, M., Schanze, I., Uebe, S., Donders, R.,... Zweier, C. (2014). Altered GPM6A/M6 Dosage Impairs Cognition and Causes Phenotypes Responsive to Cholesterol in Human and Drosophila. Human Mutation, 35(12), 1495-505. https://doi.org/10.1002/humu.22697
MLA:
Gregor, Anne, et al. "Altered GPM6A/M6 Dosage Impairs Cognition and Causes Phenotypes Responsive to Cholesterol in Human and Drosophila." Human Mutation 35.12 (2014): 1495-505.
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