SPG52 found in people with cerebral palsy

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 3Alessandra Tessa 1Valentina Naef 1Maria Teresa Bassi 4Andrea Citterio 4Romina Romaniello 5Gianluca Fichi 1Daniele Galatolo 1Serena Mero 1Roberta Battini 6Giulia Bertocci 1Jacopo Baldacci 1Federico Sicca 1 6Federica Gemignani 2Ivana Ricca 1Anna Rubegni 1Jennifer Hirst 7Maria Marchese 1Mustafa Sahin 3Darius Ebrahimi-Fakhari 3Filippo 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.

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