biostudies-literatureDiarra SCentre Hospitalier Universitaire de PoitiersIntramural NIH HHSEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNCATS NIH HHSNHGRINHGRI NIH HHSNINDS NIH HHSNational Institutes of HealthNIH Common FundNINDS106537https://www.ebi.ac.uk/biostudies/studies/S-EPMC11209852biostudies-literatureUnknown198Hereditary 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.Neurobiology of diseaseAP2A2 mutation and defective endocytosis in a Malian family with hereditary spastic paraplegia.PMC11209852Z99 NS999999ZIA HD001607UL1 TR001863U01 HG007044U01HG007044R01 NS118522R01NS118522Cisse CAKGuinto COCoulibaly OCoulibaly TMis EKFischbeck KHCisse LBlackstone CSchindler AHarmison GGrunseich CBonifacino JSLakhani SAYalcouye ASamassekou OMaiga ABDiallo SBamba SGhosh SJacobson SDonovan FXDiallo SHLandoure GDiarra SKhokha MKfalseAP2A2 mutation and defective endocytosis in a Malian family with hereditary spastic paraplegia.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.2024-01-01T00:00:00Z2024 Aug2026-07-05T03:19:10.045Z2025-08-18T09:54:15.131ZS-EPMC112098523877245210.1016/j.nbd.2024.106537