ArticleHuman molecular genetics2015
Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 62 citations in OpenAlex.
- The AP-4 accessory protein tepsin exhibits multivalent binding to LC3B.Advances in biological regulation · 2026Article
- Hereditary Spastic Paraplegy Associated with the AP4S1 Gene: A Case Series Highlighting Diagnostic Pitfalls and Phenotypic Variability.Molecular syndromology · 2025Article
- Integrated gene expression and alternative splicing analysis in human and mouse models of Rett syndrome.Scientific reports · 2025Article
- Identification of novel genetic loci related to dromedary camel (Camelus dromedarius) morphometrics, biomechanics, and behavior by genome-wide association studies.BMC veterinary research · 2024Article
- AP2A2 mutation and defective endocytosis in a Malian family with hereditary spastic paraplegia.Neurobiology of disease · 2024Article
- Tepsin binds LC3B to promote ATG9A trafficking and delivery.Molecular biology of the cell · 2024Article
- Autosomal Dominant Spastic Paraplegia With Dysregulation of Bowel Function Associated With Heterozygous AP4S1 Gene Mutation: Case Report.Neurology. Genetics · 2024Article
- The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for Hereditary Spastic Paraplegia.Progress in neurobiology · 2024Article
- Hereditary spastic paraplegia in Mali: epidemiological and clinical features.Acta neurologica Belgica · 2023Article
- AP-4 loss in CRISPR-edited zebrafish affects early embryo development.Advances in biological regulation · 2023Article
- AP-4 regulates neuronal lysosome composition, function, and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network.Molecular biology of the cell · 2022Article
- Hereditary Spastic Paraplegia: An Update.International journal of molecular sciences · 2022Review
- Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview.Frontiers in molecular biosciences · 2021Review
- Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.Brain : a journal of neurology · 2020Article
- Integrating structural and evolutionary data to interpret variation and pathogenicity in adapter protein complex 4.Protein science : a publication of the Protein Society · 2020Article
- Membrane trafficking in health and disease.Disease models & mechanisms · 2020Review
- The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A.Molecular biology of the cell · 2020Article
- Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52.Annals of clinical and translational neurology · 2020Article
- Novel variants in AP4B1 cause spastic tetraplegia, moderate psychomotor development delay and febrile seizures in a Chinese patient: a case report.BMC medical genetics · 2020Article
- Axonal autophagosome maturation defect through failure of ATG9A sorting underpins pathology in AP-4 deficiency syndrome.Autophagy · 2020Article
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Authors and funding
13 authors at 9 institutions in 7 countries.
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Abstract
We report two siblings with infantile onset seizures, severe developmental delay and spastic paraplegia, in whom whole-genome sequencing revealed compound heterozygous mutations in the AP4S1 gene, encoding the σ subunit of the adaptor protein complex 4 (AP-4). The effect of the predicted loss-of-function variants (p.Gln46Profs*9 and p.Arg97*) was further investigated in a patient's fibroblast cell line. We show that the premature stop mutations in AP4S1 result in a reduction of all AP-4 subunits and loss of AP-4 complex assembly. Recruitment of the AP-4 accessory protein tepsin, to the membrane was also abolished. In retrospect, the clinical phenotype in the family is consistent with previous reports of the AP-4 deficiency syndrome. Our study reports the second family with mutations in AP4S1 and describes the first two patients with loss of AP4S1 and seizures. We further discuss seizure phenotypes in reported patients, highlighting that seizures are part of the clinical manifestation of the AP-4 deficiency syndrome. We also hypothesize that endosomal trafficking is a common theme between heritable spastic paraplegia and some inherited epilepsies.
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