AP2A2 mutation and defective endocytosis in a Malian family with hereditary spastic paraplegia
Year: 2024
Type: article
Abstract: Hereditary spastic paraplegia (HSP) comprises a large group of neurogenetic disorders characterized by progressive lower extremity spasticity. Neurological evaluation and genetic testing were completed in a Malian family with early-onset HSP. Three children with unaffected consanguineous parents presented with symptoms consistent with childhood-onset complicated HSP. Neurological evaluation found lower limb weakness, spasticity, dysarthria, seizures, and intellectual disability. Brain MRI showed corpus callosum thinning with cortical and spinal cord atrophy, and an EEG detected slow background in the index patient. Whole exome sequencing identified a homozygous missense variant in the adaptor protein (AP) complex 2 alpha-2 subunit (AP2A2) gene. Western blot analysis showed reduced levels of AP2A2 in patient-iPSC derived neuronal cells. Endocytosis of transferrin receptor (TfR) was decreased in patient-derived neurons. In addition, we observed increased axon initial segment length in patient-derived neurons. Xenopus tropicalis tadpoles with ap2a2 knockout showed cerebral edema and progressive seizures. Immunoprecipitation of the mutant human AP-2-appendage alpha-C construct showed defective binding to accessory proteins. We report AP2A2 as a novel genetic entity associated with HSP and provide functional data in patient-derived neuron cells and a frog model. These findings expand our understanding of the mechanism of HSP and improve the genetic diagnosis of this condition.
Source: Neurobiology of Disease
Authors: Salimata Diarra, Saikat Ghosh, Lassana Cissé, Thomas Coulibaly, Abdoulaye Yalcouyé, George Harmison, Salimata Diallo, Seybou H. Diallo, Oumar Coulibaly, Alice Schindler, Cheick A.K. Cissé, Alassane B. Maiga, Salia Bamba, Oumar Samassekou, Mustafa K. Khokha, Emily K. Mis, Saquib A. Lakhani, Frank X. Donovan, Steve Jacobson, Craig Blackstone, Cheick O. Guinto, Guida Landouré, Juan S. Bonifacino, Kenneth H. Fischbeck, Christopher Grunseich
Institutions: National Institutes of Health, Yale University, National Institute of Neurological Disorders and Stroke, Université des Sciences, des Techniques et des Technologies de Bamako, Eunice Kennedy Shriver National Institute of Child Health and Human Development, University of Cape Town, National Human Genome Research Institute, Harvard University, Massachusetts General Hospital
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,430
Funders: University of Miami, Centre Hospitalier Universitaire de Poitiers, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Common Fund
OpenAlex ID: W4397289270