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; Djémié, Taniaet al.
2015 • In Human Molecular Genetics, 24 (8), p. 2218-2227
[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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) ULHPC - University of Luxembourg: High Performance Computing
Disciplines :
Genetics & genetic processes
Author, co-author :
Hardies, Katia
May, Patrick ; 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 ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly