Publication
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
Author
Institution/Organisation
AR Working Group of the EuroEPINOMICS RES Consortium
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 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 AP-4 deficiency syndrome. We also hypothesize that endosomal trafficking is a common theme between heritable spastic paraplegia and some inherited epilepsies.
Language
English
Source (journal)
Human molecular genetics. - Oxford
Publication
Oxford : 2015
ISSN
0964-6906
Volume/pages
24:8(2015), p. 2218-2227
ISI
000353066200009
Full text (Publishers DOI)
Full text (publishers version - intranet only)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 01.02.2016
Last edited 30.04.2017
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