Reference : Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, de...
Scientific journals : Article
Life sciences : Genetics & genetic processes
Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly
Hardies, Katia []
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Djémié, Tania []
Tarta-Arsene, Oana []
Deconinck, Tine []
Craiu, Dana []
EuroEPINOMICS RES Consortium []
Helbig, Ingo []
Suls, Arvid []
Balling, Rudi mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Weckhuysen, Sarah []
De Jonghe, Peter []
Hirst, Jennifer []
Human Molecular Genetics
Oxford University Press
Yes (verified by ORBilu)
United Kingdom
[en] Epilepsy ; Genetics ; Sequencing
[en] 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 sigma 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 AP4-deficiency syndrome. We also hypothesize that endosomal trafficking is a common theme between heritable spastic paraplegia and some inherited epilepsies.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) ; University of Luxembourg: High Performance Computing - ULHPC

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