- Tools
- Downloads
- Links
- Community
- About
- Help
FB2026_01
,
released March 12, 2026
It is known that the endosome/lysosome pathway is disrupted early in the course of both Down syndrome (DS) and Alzheimer disease (AD); Down syndrome individuals are also at a higher risk of developing Alzheimer disease. The three proteins in this disease model (ITSN1, SYNJ1, and RCAN1) are involved in synaptic vesicle recycling and/or development of normal synaptic morphology. All three genes map to 21q22.1-q22.2, within or near the originally defined Down syndrome critical region; RCAN1 was originally designated Down syndrome critical region gene 1 (DSCR1). For each human gene there is a single fly ortholog (many-to-one in all 3 cases; see Ortholog Information section, below).
A UAS construct of a tagged wild-type human Hsap\RCAN1 gene has been introduced into flies and has been made available; it has not been characterized. Neither ITSN1 nor SYNJ1 has been introduced into flies.
It was found that overexpression of any the individual fly orthologs (Dap160, Synj, or sra) leads to abnormal synaptic morphology; overexpression of all three genes is necessary to cause impaired vesicle recycling and locomotor defects (FBrf0208963).
[updated Apr. 2018 by FlyBase; FBrf0222196]
Down syndrome is characterized by a particular combination of phenotypic features that includes mental retardation and characteristic facial structure. Individuals with Down syndrome often have specific major congenital malformations such as those of the heart (30-40% in some studies) and of the gastrointestinal tract. 90% of Down syndrome patients have a significant hearing loss (Mazzoni et al., 1994; pubmed:7881226). A number of other diseases are observed at higher frequency among Down syndrome individuals, including leukemia (Robison, 1992; pubmed:1532221) and Alzheimer disease (Wisniewski et al., 1985; pubmed:3158266). [from MIM:190685; 2016.07.19]
Pathology of brains of individuals with Down syndrome or Alzheimer disease includes aberrant endocytosis associated with accumulation of enlarged endosomes (Xu et al., 2016; pubmed:27064279; earlier references cited in FBrf0208963).
The three proteins in this disease model are involved in synaptic vesicle recycling and/or development of normal synaptic morphology: ITSN1 (Intersectin 1) encodes a cytoplasmic membrane-associated protein that indirectly coordinates endocytic membrane traffic with the actin assembly machinery (Gene Cards, ITSN1; 2016.07.25). SYNJ1 (Synaptojanin 1) encodes a phosphoinositide phosphatase that regulates membrane proteins involved in synaptic transmission and membrane trafficking (Gene Cards, SYNJ1; 2016.07.25). RCAN1 (Regulator Of Calcineurin 1) encodes a protein that interacts with calcineurin A and inhibits calcineurin-dependent signaling pathways (Gene Cards, RCAN1; 2016.07.25). Calcineurin has been shown to dephosphorylate and stimulate the activity of synaptojanin; calcineurin inhibitors impair synaptic vesicle recycling and reduce the total vesicle pool size in synaptic terminals (references cited in FBrf0208963).
Many to one: 2 human to 1 Drosophila; the fly gene Dap160 is orthologous to ITSN1 and ITSN2 in human.
Many to one: 3 human to 1 Drosophila; the fly gene sra is orthologous to RCAN1, RCAN2, and RCAN3 in human.
Many to one: 2 human to 1 Drosophila; the fly gene Synj is orthologous to SYNJ1 and SYNJ2 in human.
High-scoring ortholog of human genes RCAN1, RCAN2, and RCAN3 (1 Drosophila to 3 human). Dmel\sra shares 33-41% identity and 49-57% similarity with the human genes.
High-scoring ortholog of human gene SYNJ1 and moderate-scoring ortholog of SYNJ2 (1 Drosophila to 2 human). Dmel\Synj shares 39-46% identity and 55-62% similarity with the human genes.
High-scoring ortholog of human genes ITSN1 and ITSN2 (1 Drosophila to 2 human). Dmel\Dap160 shares 30% identity and 44-45% similarity with the human genes.