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FB2026_01
,
released March 12, 2026
In a family with two siblings that suffered from early-onset parkinsonism with additional behavioral, intellectual, and cognitive dysfunctions, a rare variant of the SGIP1 gene was found to be homozygous in the affected individuals; heterozygous family members were not affected. SGIP1 encodes an endocytic protein known to interact with endophilins and that may function in clathrin-mediated endocytosis. The is a single orthologous gene in Drosophila, Dmel\Sgip1, for which a number of genetic reagents have been generated, including an amorphic allele, RNAi targeting constructs, and misexpression element insertions. Dmel\Sgip1 is orthologous to several other human genes, most closely to FCHO1 and FCHO2.
The human SGIP1 gene has not been introduced into flies.
Animals homozygous for an amorphic mutation of Dmel\Sgip1 survive to adulthood, but exhibit progressive behavioral and motor dysfunction, seizure-like behavior, and progressive neurodegeneration, including dopaminergic synapse loss. A mutation in the fly gene analogous to the SGIP1:p.Trp694Gly human disease-implicated variant was characterized and found to result in reduced levels of the protein product; see the 'Disease-Implicated Variants' table below.
[updated Nov. 2024 by FlyBase; FBrf0222196]
Parkinson disease (PD) is a neurodegenerative disease usually typified by slow onset in mid to late adulthood; there are also early-onset and juvenile forms of the disease. Symptoms worsen over time and include resting tremor, muscular rigidity, bradykinesia [abnormal slowness of movement], and postural instability [impaired balance and coordination]; additional symptoms may include postural abnormalities, dysautonomia [symptoms caused by malfunction of the autonomic nervous system], dystonic cramps, and dementia. Parkinson disease is the second-most common neurodegenerative disease (after Alzheimer disease), affecting approximately 1% of the population over 50 (Polymeropoulos et al., 1996, pubmed:8895469). [from MIM:168600; 2013.07.23]
Parkinson disease is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 may be referred to as juvenile-onset disease. [from Genetics Home Reference, GHR_condition:parkinson-disease, 2015.02.13]
In the two described cases (from one family), symptoms of parkinsonism developed in early adulthood; non-motor symptoms included behavioral, intellectual, and cognitive dysfunction; one individual experienced generalized tonic clonic seizures in childhood (Decet et al., 2024; pubmed:39332416; FBrf0260723).
Multiple genes associated with early-onset Parkinson disease were screened, but none exhibited clinically significant mutations. A missense mutation in the SGIP1 gene was found to be homozygous in the two affected individuals; several unaffected family members were found to be heterozygous for the SGIP1 variant (Decet et al., 2024; pubmed:39332416; FBrf0260723). The disease-implicated variant was absent from the main variation databases (Decet et al., 2024).
SGIP1 encodes an endocytic protein that affects signaling by receptors in neuronal systems involved in energy homeostasis via its interaction with endophilins; it may function in clathrin-mediated endocytosis. It is variously described as SH3GL Interacting Protein 1, SH3GL Interacting Endocytic Adaptor 1, and Endophilin-3-Interacting Protein. [GeneCards, SGIP1; 2024.11.19]
Many to one: 3 human genes to 1 Drosophila gene.
High-scoring ortholog of human FCHO1, FCHO2, and SGIP1 (1 Drosophila to 3 human).