Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52

Ann Clin Transl Neurol. 2020 Apr;7(4):584-589. doi: 10.1002/acn3.51018. Epub 2020 Mar 25.


Autosomal recessive spastic paraplegia 52 is caused by biallelic mutations in AP4S1 which encodes a subunit of the adaptor protein complex 4 (AP-4). Using next-generation sequencing, we identified three novel unrelated SPG52 patients from a cohort of patients with cerebral palsy. The discovered variants in AP4S1 lead to reduced AP-4 complex formation in patient-derived fibroblasts. To further understand the role of AP4S1 in neuronal development and homeostasis, we engineered the first zebrafish model of AP-4 deficiency using morpholino-mediated knockdown of ap4s1. In this model, we discovered several phenotypes mimicking SPG52, including altered CNS development, locomotor deficits, and abnormal neuronal excitability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 4 / deficiency
  • Adaptor Protein Complex 4 / genetics*
  • Adolescent
  • Animals
  • Animals, Genetically Modified
  • Behavior, Animal / physiology
  • Cerebral Palsy / genetics
  • Child, Preschool
  • Cohort Studies
  • Disease Models, Animal
  • Epilepsy / genetics
  • Epilepsy / physiopathology
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / physiopathology*
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / physiopathology*
  • Zebrafish


  • AP4S1 protein, human
  • Adaptor Protein Complex 4