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FB2026_01
,
released March 12, 2026
This report describes a neurodevelopmental disorder associated with the human gene IRF2BPL, 'neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures' (NEDAMSS). NEDAMSS exhibits autosomal dominant inheritance. IRF2BPL (interferon regulatory factor 2 binding protein like) is not a well-characterized gene; it appears to act as a transcriptional activator in multiple tissues, including the nervous system. There is a single orthologous gene in Drosophila, Pits, for which a loss-of-function (probably amorphic) allele generated by targeted recombination, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Pits is also orthologous to two related human genes, IRF2BP1 and IRF2BP2.
Multiple UAS constructs of the human Hsap\IRF2BPL gene have been introduced into flies, including wild-type and variants associated with disease. Ubiquitous overexpression of Hsap\IRF2BPL results in lethality; overexpression of transgenic constructs with disease-associated variants has allowed assessment of level of residual function of IRF2BPL in each case. Variant(s) implicated in human disease tested (as transgenic human gene, IRF2BPL): the E172*, Q127*, R188*, P372R, and K418N variant forms have been introduced into flies.
Males hemizygous for a severe loss-of-function allele of Dmel\Pits die in the embryonic or first larval instar stage. Ubiquitous overexpression of Pits also results in lethality. Partial knockdown Pits, effected by RNAi, results in viable adults with progressive behavior defective phenotypes, including locomotor defects and bang-sensitivity. Dmel\Pits exhibits high levels of expression in neurons, but not glia, of the larval and adult CNS, including the brain. A small number of physical and genetic interactions have been described for Dmel\Pits; see below and in the Pits gene report.
[updated Aug. 2018 by FlyBase; FBrf0222196]
[NEURODEVELOPMENTAL DISORDER WITH REGRESSION, ABNORMAL MOVEMENTS, LOSS OF SPEECH, AND SEIZURES; NEDAMSS](https://omim.org/entry/618088)
[INTERFERON REGULATORY FACTOR 2-BINDING PROTEIN LIKE; IRF2BPL](https://omim.org/entry/611720)
Marcogliese et al. (2018, pubmed:30057031) reported 7 unrelated patients, ranging in age from 2.5 to 43 years, with a neurodevelopmental disorder. Five patients had a more severe disorder characterized by neurodevelopmental regression that became apparent between 2 and 10 years of age after normal early development in most patients, although a few had mild early delays. These patients presented with difficulties walking that progressed to loss of independent walking; all became wheelchair-bound. They also lost language skills and fine and gross motor skills, and developed severe dysphagia requiring tube feeding, facial weakness, and dysarthria. [from MIM:618088; 2018.08.30]
NEDAMSS is caused by heterozygous mutation in the IRF2BPL gene (Marcogliese et al., 2018; pubmed:30057031). [from MIM:618088; 2018.08.30]
The architecture of IRF2BPL and Dmel\Pits is very similar and the sequences of identified domains show high conservation: 79% identity for the zinc-finger domain, 76% identity for the C3HC4 RING domain (FBrf0239685).
The IRF2BPL gene encodes a protein that is expressed in many organs, including the central nervous system. Evidence suggests that it acts as a transcriptional activator and may also function as an E3 ubiquitin ligase (summary by Marcogliese et al., 2018; pubmed:30057031). [from MIM:611720; 2018.08.30]
Many to one: 3 human to 1 Drosophila; the human genes are IRF2BPL, IRF2BP1, and IRF2BP2.
High-scoring ortholog of human IRF2BPL, IRF2BP1, and IRF2BP2 (1 Drosophila to 3 human). Dmel\Pits shares 30-32% identity and 36-41% similarity with the human genes.