Transient and lineage-restricted requirement of Ebf3 for sternum ossification

Kuriki, Mao; Sato, Fuminori; Arai, Hiroyuki; Sogabe, Maina; Kaneko, Mari; Kanazawa, Hiroshi; Kawakami, Koichi; Yoshimoto, Yuki; Shukunami, Chisa; Sehara-Fujisawa, Atsuko

doi:10.1242/dev.186239

Cited by 6 publications

(13 citation statements)

References 42 publications

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“…Anatomical findings in our study included abnormal kidney or bladder anatomy (33%, CI [17,49], OR=2.9), vesicoureteric reflux (18%, CI [5,31] (Fig.3D), which had a similar frequency in the meta-analysis. Female reproductive organ anomalies were seen in 6% of the meta-analysis (Table S2) but were not observed in our cohort ( Table S1).…”

Section: Pathogenic Ebf3 Variants and Genomic Deletionssupporting

confidence: 54%

“…Consistent with the neurodevelopmental impairments, neuroimaging studies in our cohort revealed altered cerebellar structure in 33% (CI [17,49]) of individuals, compared to 18% (CI [9,38]) in the meta-analysis (OR=1.63, Fig.2H). Cerebellar vermian hypoplasia was observed in 30% (CI [15,46]) of individuals in our study, compared to 18% (CI [5,30] compared to a meta-analysis frequency of 12-21% for these features (Fig.3C). Genitourinary complications are frequently observed in both males and females.…”

Section: Pathogenic Ebf3 Variants and Genomic Deletionscontrasting

confidence: 46%

“…Early B-Cell Factor 3 (EBF3; OMIM*607407; HGNC:19087) encodes a Collier/Olf/EBF (COE) transcription factor located on chromosome 10q26. COE transcription factors control gene expression via DNA methylation, nucleosome remodeling, and active chromatin modifications [1][2][3] , and regulate nervous system, immune system, bone, and muscle development [4][5][6][7] . Loss-offunction manipulations of EBF3 homologs in worms (unc-3, CeO/E), flies (knot, collier), frogs (Xcoe2), and mice (Ebf3) are deleterious to survival and impair neurodevelopment 8 .…”

Section: Introductionmentioning

confidence: 99%

“…The comprehensive phenotypic analysis also revealed a high frequency of motor incoordination (63%, CI[47, 80], OR=8.17), hypomimia (57%, CI[40, 74], OR=7.87), and hypertonia (39%, CI[22, 56], OR=21.45), but these features were reported in less than 20% of affected individuals in the meta-analysis (Fig.2C). Additional neurologic findings include an increased risk of seizures (39%, CI[22, 56], OR=21.45), febrile seizures (28%, CI[13, 43], OR=3.875), and abnormalities on electroencephalogram (EEG) recordings (18%, CI[5,31] OR=1.04) (Fig.2D). Intriguingly, we found that altered sensory processing is a cardinal feature of HADDS.…”

mentioning

confidence: 99%

“…Other sensory findings in our cohort include repetitive scratching behaviors (51%, CI[34, 69]), hyperacusis (48%, CI[31, 66]), and discomfort with loud noises (45%, CI[28, 62]) (Fig.2E), all of which were not previously reported.Neuropsychiatric comorbidities are commonly observed in affected individuals with HADDS.We found that these features occur at a higher frequency than previously reported. Prevalent neuropsychiatric comorbidities in HADDS include autistic features (52%, CI[34, 69], OR=17.6), formal autism diagnosis (27%, CI[12, 42], OR=8.82), attention deficit and hyperactivity disorder (ADHD, 18%, CI[5,31], OR=1.03), and emotional lability (18%, CI[5,31], OR=3.56)(Fig.2F). Common autistic features identified in our study include stereotypies (63%, CI [47, 80], OR=11.8), poor eye contact (39%, CI[23, 56]), attraction to lights (24%, CI[10,39]), and aversion to crowds (21%, CI[7,35]) (Fig.…”

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confidence: 99%

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Integrated phenotypic and mutational approach defines EBF3-related HADD syndrome genotype-phenotype relationships

Deisseroth

Nayak

Bliss

et al. 2020

Preprint

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Hypotonia, Ataxia, and Delayed Development syndrome is a neurodevelopmental disorder caused by heterozygous Early B-Cell Factor 3 (EBF3) loss-of-function variants. Identified in 2016, the full spectrum of clinical findings and the relationship between the EBF3 genotype and clinical outcomes has not been determined beyond its namesake features. We combined a phenotypic assessment of 33 individuals molecularly diagnosed with EBF3 pathogenic variants with a meta-analysis of 34 previously reported individuals. The combined 62 unique individuals enabled comparative cross-sectional phenotype and genotype analysis in the largest cohort to date of affected individuals. Cardinal distinguishing features were identified that facilitate phenotypic stratification for clinical diagnosis. We developed assessment scales to ascertain individuals at risk for pathogenic EBF3 variants, stratify the clinical severity, and connect variant-specific molecular phenotypes to clinical outcomes. Our findings show that a specific class of EBF3 variants affecting the evolutionarily conserved Zinc Finger (ZNF) motif, which is critical for stabilizing the protein interaction with the DNA target sequence, is associated with an increased risk of persistent motor and language impairments. These findings highlight the impact of combining variant-specific molecular phenotypes with comprehensive clinical data to predict neurodevelopmental outcomes and potentially guide personalized decisions for therapeutic interventions.

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Section: Pathogenic Ebf3 Variants and Genomic Deletionssupporting

confidence: 54%

Section: Pathogenic Ebf3 Variants and Genomic Deletionscontrasting

confidence: 46%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Integrated phenotypic and mutational approach defines EBF3-related HADD syndrome genotype-phenotype relationships

Deisseroth

Nayak

Bliss

et al. 2020

Preprint

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An Integrated Phenotypic and Genotypic Approach Reveals a High‐Risk Subtype Association for EBF3 Missense Variants Affecting the Zinc Finger Domain

Deisseroth

Lerma

Magyar

et al. 2022

Annals of Neurology

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Objective: Collier/Olf/EBF (COE) transcription factors have distinct expression patterns in the developing and mature nervous system. To date, a neurological disease association has been conclusively established for only the Early B-cell Factor-3 (EBF3) COE family member through the identification of heterozygous loss-of-function variants in individuals with autism spectrum/neurodevelopmental disorders (NDD). Here, we identify a symptom severity risk association with missense variants primarily disrupting the zinc finger domain (ZNF) in EBF3-related NDD. Methods: A phenotypic assessment of 41 individuals was combined with a literature meta-analysis for a total of 83 individuals diagnosed with EBF3-related NDD. Quantitative diagnostic phenotypic and symptom severity scales were developed to compare EBF3 variant type and location to identify genotype-phenotype correlations. To stratify the effects of EBF3 variants disrupting either the DNA-binding domain (DBD) or the ZNF, we used in vivo fruit fly UAS-GAL4 expression and in vitro luciferase assays. Results: We show that patient symptom severity correlates with EBF3 missense variants perturbing the ZNF, which is a key protein domain required for stabilizing the interaction between EBF3 and the target DNA sequence. We found that ZNFassociated variants failed to restore viability in the fruit fly and impaired transcriptional activation. However, the recurrent variant EBF3 p.Arg209Trp in the DBD is capable of partially rescuing viability in the fly and preserved transcriptional activation. Interpretation: We describe a symptom severity risk association with ZNF perturbations and EBF3 loss-of-function in the largest reported cohort to date of EBF3-related NDD patients. This analysis should have potential predictive clinical value for newly identified patients with EBF3 gene variants.

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Incoherent collective cell chemotaxis in a zebrafish model of branchio-oto-renal syndrome

Miranda-Rodríguez

Borges

Pinto-Teixeira

et al. 2021

Preprint

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SUMMARYTissue remodeling presents an enormous challenge to the stability of intercellular signaling domains. Here we investigate this issue during the development of the posterior lateral line in zebrafish. We find that the transcriptional co-activator and phosphatase Eya1, mutated in the branchio-oto-renal syndrome in humans, is essential for the homeostasis of the Wnt/β-catenin and FGF morphogenetic domains during the collective migration of lateral-line primordial cells. Loss of Eya1 strongly diminishes the expression of Dkk1, expanding Wnt/β-catenin activity in the primordium, which in turn abrogates FGFR1 expression. Deficits in Eya1 also abolishes the expression of the chemokine receptor CXCR7b, disrupting primordium migration. These results reinforce the concept that morphogenetic domains in dynamically remodeling tissues are formed by cellular states maintained by continuous signaling.

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Transient and lineage-restricted requirement of Ebf3 for sternum ossification

Cited by 6 publications

References 42 publications

Integrated phenotypic and mutational approach defines EBF3-related HADD syndrome genotype-phenotype relationships

Integrated phenotypic and mutational approach defines EBF3-related HADD syndrome genotype-phenotype relationships

An Integrated Phenotypic and Genotypic Approach Reveals a High‐Risk Subtype Association for EBF3 Missense Variants Affecting the Zinc Finger Domain

Incoherent collective cell chemotaxis in a zebrafish model of branchio-oto-renal syndrome

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