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: Katia Hardies, Patrick May, Tania Djémié, Oana Tarta-Arsene, Tine Deconinck, Dana Craiu, AR working group of the EuroEPINOMICS RES Consortium, Ingo Helbig, Arvid Suls, Rudy Balling, Sarah Weckhuysen, Peter De Jonghe, Jennifer Hirst
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 8 Pg. 2218-27 (Apr 15 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25552650 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• AP4S1 protein, human
• Adaptor Protein Complex 4
• Codon, Nonsense

Topics

• Adaptor Protein Complex 4 (genetics, metabolism)
• Adolescent
• Base Sequence
• Child
• Child Development
• Child, Preschool
• Codon, Nonsense (genetics, metabolism)
• Female
• Genes, Recessive
• Heterozygote
• Humans
• Male
• Molecular Sequence Data
• Mutation
• Seizures, Febrile (genetics, metabolism, physiopathology)
• Spastic Paraplegia, Hereditary (genetics, metabolism, physiopathology)
• Young Adult