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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 theGPM6Agene in a patient with learning disability and behavioral anomalies. Expression analysis in blood lymphocytes showed increasedGPM6Alevels. An increase of patient-derived lymphoblastoid cells carrying membrane protrusions supports a functional effect of this duplication. To study the consequences ofGPM6Adosage alterations in an intact nervous system, we employedDrosophila melanogasteras a model organism. We found that knockdown ofDrosophilaM6, 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 theGPM6Aduplication for the patient's phenotype. Together with other recent findings, this study highlights compromised cholesterol homeostasis as a recurrent feature in cognitive phenotypes.We found a de novo duplication of GPM6A in a patient with learning disability and behavioral problems. Altered dosage of human GPM6A in patient lymphoblastoid cells caused an increased presence of cells carrying membrane protrusions, while tissue specific dosage manipulation of the fly counterpart M6 resulted in wing defects, lethality and impaired memory in Drosophila. We could improve some of these by supplementation of cholesterol. Our findings further emphasize a role of cholesterol in cognitive function and dysfunction.