Neurodevelopmental disorder caused by a truncating de novo variant of IRF2BPL

Qian, Xiaohang; Li, Xiaoying; Zhu, Zeyu; Wang, Shi-Ge; Song, Xiaoxuan; Chen, Guang; Wu, Jingying; Tang, Huidong; Cao, Li

doi:10.1016/j.seizure.2020.11.006

Cited by 11 publications

(22 citation statements)

References 20 publications

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“…This leads to agedependent phenotypes in flies that are reminiscent of the progressive phenotypes observed in patients with truncations of IRF2BPL. Individuals with NEDAMSS often progress in development as expected for their age, and the onset of symptoms usually does not occur until the mean age of 5, with some cases only developing disease signs in adolescence (1,2,(36)(37)(38)(39)(40)(41)(42)(43)(44). Decline in motor skills continues until patients become fully dependent of caretakers.…”

Section: Discussionmentioning

confidence: 99%

Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling

et al. 2022

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De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like ( IRF2BPL ) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of IRF2BPL causes neural dysfunction, we examined its function in Drosophila and zebrafish. Overexpression of either IRF2BPL or Pits , the Drosophila ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased wingless ( wg ) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of wg in flies is sufficient to cause age-dependent axonal loss, similar to reduction of Pits. Loss of irf2bpl in zebrafish also causes neurological defects with an associated increase in wnt1 transcription and downstream signaling. WNT1 is also increased in patient-derived astrocytes, and pharmacological inhibition of Wnt suppresses the neurological phenotypes. Last, IRF2BPL and the Wnt antagonist, CKIα, physically and genetically interact, showing that IRF2BPL and CkIα antagonize Wnt transcription and signaling.

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Section: Discussionmentioning

confidence: 99%

Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling

et al. 2022

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“…Given that NEDAMSS primarily affects the nervous system and presents with various neurological symptoms in patients, 8,9,12 we explored the cell morphology and expression levels of IRF2BPL in neurons. We utilized an established direct conversion method using small molecules to generate iNs from fibroblasts.…”

Section: Full-length Irf2bpl Is Mislocalized To the Cytoplasm In Neda...mentioning

confidence: 99%

“…7 Recently, heterozygous truncating mutations in IRF2BPL have been shown to cause variable neurological phenotypes, indicating that the gene might play an important role in both devel-opment and neuronal maintenance. [8][9][10][11][12] Missense variants have also been reported but are mostly associated with milder neurological symptoms such as seizures, developmental delay, and autistic spectrum disorder. 8 Most severely affected individuals have typical initial development until around 3.5 years of age, at which point developmental delay and neurological regression occur, leading to abnormal movements, loss of motor skills and speech, and seizures.…”

Section: Introductionmentioning

confidence: 99%

“…8 Most severely affected individuals have typical initial development until around 3.5 years of age, at which point developmental delay and neurological regression occur, leading to abnormal movements, loss of motor skills and speech, and seizures. 8,9,12 The disorder has since been termed NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM: 618088). Since the discovery of this disease in 2018, 25 patients have been reported worldwide 12 with IRF2BPL mutations causing NEDAMSS, but increased genetic testing for this rare disease will likely unravel a higher frequency.…”

Section: Introductionmentioning

confidence: 99%

“…8,9,12 The disorder has since been termed NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM: 618088). Since the discovery of this disease in 2018, 25 patients have been reported worldwide 12 with IRF2BPL mutations causing NEDAMSS, but increased genetic testing for this rare disease will likely unravel a higher frequency. 13 Little is known about IRF2BPL function in the nervous system.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy

et al. 2022

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Genetic analysis of IRF2BPL in a Taiwanese dystonia cohort: The genotype and phenotype correlation

Chen,

Chiu

et al. 2024

Ann Clin Transl Neurol

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ObjectiveIRF2BPL mutation has been associated with a rare neurodevelopmental disorder with abnormal movements, including dystonia. However, the role of IRF2BPL in dystonia remains elusive. We aimed to investigate IRF2BPL mutations in a Taiwanese dystonia cohort.MethodsA total of 300 unrelated patients with molecularly unassigned isolated (n = 256) or combined dystonia (n = 44) were enrolled between January 2015 and July 2023. The IRF2BPL variants were analyzed based on whole exome sequencing. The in silico prediction of the identified potential pathogenic variant was performed to predict its pathogenicity. We also compared the clinical and genetic features to previous literature reports.ResultsWe identified one adolescent patient carrying a de novo heterozygous pathogenic variant of IRF2BPL, c.379C>T (p.Gln127Ter), who presented with generalized dystonia, developmental regression, and epilepsy (0.33% of our dystonia cohort). This variant resides within the polyglutamine (poly Q) domain before the first PEST sequence block of the IRF2BPL protein, remarkably truncating the protein structure. Combined with other patients with IRF2BPL mutations in the literature (n = 60), patients with variants in the poly Q domain have a higher rate of nonsense mutations (p < 0.001) and epilepsy (p = 0.008) than patients with variants in other domains. Furthermore, as our index patient, carriers with substitutions before the first PEST sequence block have significantly older age of onset (p < 0.01) and higher non‐epilepsy symptoms, including generalized dystonia (p = 0.003), and ataxia (p = 0.003).InterpretationIRF2BPL mutation is a rare cause of dystonia in our population. Mutations in different domains of IRF2BPL exhibit different phenotypes.

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Neurodevelopmental disorder caused by a truncating de novo variant of IRF2BPL

Cited by 11 publications

References 20 publications

Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling

Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling

Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy

Genetic analysis of IRF2BPL in a Taiwanese dystonia cohort: The genotype and phenotype correlation

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