Three new mutations identified
Amongst a group of patients with cerebral palsy in this Italian study, three were identified as having mutations in the AP4S1 gene associated with SPG52, a complicated form of HSP. The researchers studied the equivalent gene in zebrafish and found equivalent symptoms mimicking human SPG52.
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.
SOURCE: Ann Clin Transl Neurol.2020 Apr;7(4):584-589. doi: 10.1002/acn3.51018. Epub 2020 Mar 25. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. PMID: 32216065
Loss of ap4s1 in Zebrafish Leads to Neurodevelopmental Defects Resembling Spastic Paraplegia 52
Angelica D’Amore 1 2 3, Alessandra Tessa 1, Valentina Naef 1, Maria Teresa Bassi 4, Andrea Citterio 4, Romina Romaniello 5, Gianluca Fichi 1, Daniele Galatolo 1, Serena Mero 1, Roberta Battini 6, Giulia Bertocci 1, Jacopo Baldacci 1, Federico Sicca 1 6, Federica Gemignani 2, Ivana Ricca 1, Anna Rubegni 1, Jennifer Hirst 7, Maria Marchese 1, Mustafa Sahin 3, Darius Ebrahimi-Fakhari 3, Filippo M Santorelli 1
1 Department of Molecular Medicine, IRCCS Stella Maris Foundation, Pisa, Italy.
2 Department of Biology, University of Pisa, Pisa, Italy.
3 Department of Neurology & The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA.
4 Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Bosisio Parini, Lecco, Italy.
5 Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.
6 Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy.
7 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.