title: Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly.
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.
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Katia
authors.initials: K
authors.lastname: Hardies
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg, Institute for Systems Biology, Seattle, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: May
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Tania
authors.initials: T
authors.lastname: Djémié
authors.affiliation: Pediatric Neurology Clinic, Al Obregia Hospital, Bucharest, Romania, Department of Neurology, Pediatric Neurology, Psychiatry, Child and Adolescent Psychiatry, and Neurosurgery, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
authors.forename: Oana
authors.initials: O
authors.lastname: Tarta-Arsene
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.affiliation: Pediatric Neurology Clinic, Al Obregia Hospital, Bucharest, Romania, Department of Neurology, Pediatric Neurology, Psychiatry, Child and Adolescent Psychiatry, and Neurosurgery, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
authors.forename: Dana
authors.initials: D
authors.lastname: Craiu
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany, Division of Neurology, The Children's Hospital of Philadelphia, Philadephia, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Rudy
authors.initials: R
authors.lastname: Balling
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium, Division of Neurology, Antwerp University Hospital, Antwerp, Belgium and peter.dejonghe@molgen.vib-ua.be.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hirst
mesh_terms: D033964:Adaptor Protein Complex 4 / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002657:Child Development; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D003294:Seizures, Febrile / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D055815:Young Adult
chemical_list: C000604469:AP4S1 protein, human; D033964:Adaptor Protein Complex 4; D018389:Codon, Nonsense