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FB2026_01
,
released March 12, 2026
This report describes a newly characterized disease, developmental and epileptic encephalopathy 109 (DEE109); DEE109 exhibits autosomal dominant inheritance. The human gene implicated in DEE109 is FZR1; thus far, characterized cases appear to the be result of de novo variants. FZR1 encodes a protein that interacts with the anaphase-promoting complex/cyclosome; it acts during various steps in the mitotic cell cycle. There are 2 orthologous genes in Drosophila, fzr and fzr2; fzr is more closely related. Multiple genetic reagents have been generated for Dmel\fzr, including loss-of-function mutations, CRISPR-generated amorphic mutations, RNAi targeting constructs, and overexpression constructs.
The human FZR1 gene has not been introduced into flies.
Mutations analogous to variants implicated in DEE have been introduced into the Dmel\fzr gene; see the 'Disease-Implicated Variants' table below. The DEE-associated variants fail to rescue photoreceptor pattern and glial cell migration phenotypes observed in fzr loss-of-function alleles. Expression of a wild-type fzr cDNA is able to partially rescue the embryonic lethality of an amorphic fzr allele; cDNAs carrying one of the disease-implicated variants fail to do so.
[updated Jul. 2023 by FlyBase; FBrf0222196]
[DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 109; DEE109](https://omim.org/entry/620145)
[FIZZY AND CELL DIVISION CYCLE 20-RELATED PROTEIN 1; FZR1](https://omim.org/entry/603619)
All three individuals carrying de novo variants in FZR1 had childhood-onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the developmental and epileptic encephalopathy subtype myoclonic atonic epilepsy. (Manivannan et al., 2022; pubmed:34788397; FBrf0253658).
Developmental and epileptic encephalopathy-109 (DEE109) is characterized by the onset of various types of seizures in the first months or years of life. Affected individuals show developmental delay before and concurrent with the onset of seizures. Features include impaired intellectual development with poor speech, ataxic gait, coordination problems, and behavioral abnormalities (Manivannan et al., 2022; pubmed:34788397). [from MIM:620145; 2022.12.23]
Developmental and epileptic encephalopathy-109 (DEE109) is caused by heterozygous mutation in the FZR1 gene .[from MIM:620145; 2022.12.23]
FZR1 encodes a protein that interacts with the anaphase-promoting complex/cyclosome (APC/C). Associates with the APC/C in late mitosis, in replacement of CDC20, and activates the APC/C during anaphase and telophase. Following DNA damage, it is required for the G2 DNA damage checkpoint. [Gene Cards, FZR1; 2022.08.02]
One to many: 1 human gene to 2 Drosophila genes.
High-scoring ortholog of human FZR1 (2 Drosophila to 1 human). A second Drosophila gene, fzr2, is a moderate-scoring ortholog of human FZR1.