A candidate loss-of-function variant in SGIP1 causes synaptic dysfunction and recessive parkinsonism

• DOI: 10.1016/j.xcrm.2024.101749
• Publication Date: 2024-09-26T15:45:58Z
• Authors: Marianna Decet; Patrick Scott; Sabine Kuenen; Douja Meftah; Jef Swerts; Carles Calatayud; Sandra F. Gallego; Natalie Kaempf; Eliana Nachman; Roman Praschberger; Nils Schoovaerts; Chris C. Tang; David Eidelberg; Samir Al Adawi; Abdullah Al Asmi; Ramachandiran Nan...; Patrik Verstreken
• Keywords: Male; Adult; synaptic proteostasis; Genes, Recessive; Synaptic Transmission; multivesicular body; Article; Pedigree; Consanguinity; Drosophila melanogaster; Parkinsonian Disorders; Loss of Function Mutation; SGIP1 variant; Synapses; Mutation; Humans; Animals; Female; young-onset parkinsonism; seizures

Synaptic dysfunction is recognized as an early step in the pathophysiology of parkinsonism. Several genetic mutations affecting the integrity of synaptic proteins cause or increase the risk of developing disease. We have identified a candidate causative mutation in synaptic "SH3GL2 Interacting Protein 1" (SGIP1), linked to early-onset parkinsonism in a consanguineous Arab family. Additionally, affected siblings display intellectual, cognitive, and behavioral dysfunction. Metabolic network analysis of [18F]-fluorodeoxyglucose positron emission tomography scans shows patterns very similar to those of idiopathic Parkinson's disease. We show that the identified SGIP1 mutation causes a loss of protein function, and analyses in newly created Drosophila models reveal movement defects, synaptic transmission dysfunction, and neurodegeneration, including dopaminergic synapse loss. Histology and correlative light and electron microscopy reveal the absence of synaptic multivesicular bodies and the accumulation of degradative organelles. This research delineates a putative form of recessive parkinsonism, converging on defective synaptic proteostasis and opening avenues for diagnosis, genetic counseling, and treatment.