title: Altered GPM6A/M6 dosage impairs cognition and causes phenotypes responsive to cholesterol in human and Drosophila.
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.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Gregor
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Kramer
authors.forename: Monique
authors.initials: M
authors.lastname: van der Voet
authors.forename: Ina
authors.initials: I
authors.lastname: Schanze
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.forename: Rogier
authors.initials: R
authors.lastname: Donders
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Annette
authors.initials: A
authors.lastname: Schenck
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D018628:Gene Dosage; D020440:Gene Duplication; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008124:Locomotion; D008562:Membrane Glycoproteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D012726:Sexual Behavior, Animal
chemical_list: C484158:GPM6A protein, human; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D002784:Cholesterol
keywords: Drosophila melanogaster; GPM6A; cognition; learning disability