Novel de novo variant in <i>EBF3</i> is likely to impact DNA binding in a patient with a neurodevelopmental disorder and expanded phenotypes: patient report, in silico functional assessment, and review of published cases

Blackburn, Patrick R.; Barnett, Sarah S.; Zimmermann, Michael T.; Cousin, Margot A.; Kaiwar, Charu; Vairo, Filippo Pinto e; Niu, Zhiyv; Ferber, Matthew J.; Urrutia, Raúl; Selcen, Duygu; Klee, Eric W.; Pichurin, Pavel N.

doi:10.1101/mcs.a001743

Cited by 23 publications

(24 citation statements)

References 37 publications

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“…The splice site variant, c.486-1G>A, may also cause the loss of the splice acceptor site and induce skipping of exon 6, which encodes the conserved zinc knuckle motif in the COE1 DBD. Molecular modeling of EBF3 mutations at the zinc knuckle has demonstrated decreased DNA affinity resulting in aberrant DNA binding ( Blackburn et al 2017 ). Altered expression or binding of EBF3 is likely responsible for the predominance of neurological symptoms seen in our patients.…”

Section: Discussionmentioning

confidence: 99%

“…EBF3 is within a shared deletion of Chromosome 10q26.3 in many of these patients. Four recent reports identified a total of 20 unrelated individuals and two siblings who have de novo variants in EBF3 and a distinct neurodevelopmental syndrome ( Blackburn et al 2017 ; Chao et al 2017 ; Harms et al 2017 ; Sleven et al 2017 ). Here we add further evidence for the role of EBF3 in brain development and expand the phenotype of this syndrome caused by pathogenic variants in EBF3 .…”

Section: Introductionmentioning

confidence: 99%

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De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism

Tanaka

Cho²,

Willaert³

et al. 2017

Cold Spring Harb Mol Case Stud

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Using whole-exome sequencing, we identified seven unrelated individuals with global developmental delay, hypotonia, dysmorphic facial features, and an increased frequency of short stature, ataxia, and autism with de novo heterozygous frameshift, nonsense, splice, and missense variants in the Early B-cell Transcription Factor Family Member 3 (EBF3) gene. EBF3 is a member of the collier/olfactory-1/early B-cell factor (COE) family of proteins, which are required for central nervous system (CNS) development. COE proteins are highly evolutionarily conserved and regulate neuronal specification, migration, axon guidance, and dendritogenesis during development and are essential for maintaining neuronal identity in adult neurons. Haploinsufficiency of EBF3 may affect brain development and function, resulting in developmental delay, intellectual disability, and behavioral differences observed in individuals with a deleterious variant in EBF3.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism

Tanaka

Cho²,

Willaert³

et al. 2017

Cold Spring Harb Mol Case Stud

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“…We found, in mice, that mEbf1 and mEbf2 are implicated in axial MN development. In the embryonic mouse spinal cord, mEbf1 is selectively expressed in hypaxial muscle-innervating MNs (HMC), while mEbf2 is expressed in epaxial muscle-innervating MNs [17,[42][43][44][45][46], our findings could help advance our understanding of these conditions.…”

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confidence: 80%

An ancient role for Collier/Olf/Ebf (COE)-type transcription factors in axial motor neuron development

Catela

Correa

Aburas

et al. 2018

Preprint

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Background: Mammalian motor circuits display remarkable cellular diversity with hundreds of motor neuron (MN) subtypes innervating hundreds of different muscles. Extensive research on limb muscle-innervating MNs has begun to elucidate the genetic programs that control animal locomotion. In striking contrast, the molecular mechanisms underlying the development of axial muscle-innervating MNs, which control breathing and spinal alignment, are poorly studied. Methods:Our previous studies indicated that the function of the Collier/Olf/Ebf (COE) family of transcription factors (TFs) in axial MN development may be conserved from nematodes to simple chordates. Here, we examine the expression pattern of all four mouse COE family members (mEbf1-mEbf4) in spinal MNs and employ genetic approaches in both nematodes and mice to investigate their function in axial MN development. Results:We report that mEbf1 and mEbf2 are expressed in distinct MN clusters (termed "columns") that innervate different axial muscles. Mouse Ebf1 is expressed in MNs of the hypaxial motor column (HMC), which is necessary for breathing, while mEbf2 is expressed in MNs of the medial motor column (MMC) that control spinal alignment. Our characterization of Ebf2 knock-out mice revealed a requirement for Ebf2 in the differentiation of a subset of MMC MNs, indicating molecular diversity within MMC neurons. Intriguingly, transgenic expression of mEbf1 or mEbf2 can rescue axial MN differentiation and locomotory defects in nematodes (Caenorhabditis elegans) lacking unc-3, the sole C. elegans ortholog of the COE family, suggesting functional conservation among mEbf1, mEbf2 and nematode UNC-3. Conclusions:These findings support the hypothesis that the genetic programs controlling axial MN development are deeply conserved across species, and further advance our understanding of such programs by revealing an essential role for Ebf2 in mouse axial MNs.Because human mutations in COE ortholgs lead to neurodevelopmental disorders characterized by motor developmental delay, our findings may advance our understanding of these human conditions.3 BACKGROUND The mammalian neuromuscular system is essential for distinct motor behaviors ranging from locomotion and dexterity to basic motor functions, such as breathing and maintenance of spinal alignment [1]. The underlying basis for achieving these diverse outputs lies in the assembly of distinct neuronal circuits dedicated to control different muscles. In the mouse spinal cord, for example, these circuits are composed of various motor neuron (MN) subtypes organized into distinct clusters of cells (termed "columns") along the rostrocaudal axis ( Fig. 1A). At the brachial and lumbar levels, MNs of the lateral motor column (LMC) innervate limb muscles, which are essential for locomotion and dexterity [2,3]. Breathing is controlled by cervical MNs of the phrenic motor column (PMC) that innervate the diaphragm, and by thoracic MNs of the hypaxial motor column (HMC) that innervate hypaxial (intercostal and abdominal) muscles. In...

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“…Greater function and mechanistic resolution are required in order to properly treat patients with these variants. Previous studies by our lab [ 33 , 34 ] and others [ 35 , 36 ] have demonstrated that computational studies can generate novel data to strongly support the interpretation of variants identified from high-throughput sequencing and also to generate detailed mechanistic hypotheses for their underlying atomic mechanisms. When paired with detailed computational analysis, candidate mechanisms can be proposed at the atomic level to unify experimental observations with prior knowledge from the literature into a coherent mechanism of molecular dysfunction, driven by genetic variants.…”

Section: Discussionmentioning

confidence: 99%

Molecular modeling of LDLR aids interpretation of genomic variants

Klee

Zimmermann

2019

J Mol Med

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Genetic variants in low-density lipoprotein receptor (LDLR) are known to cause familial hypercholesterolemia (FH), occurring in up to 1 in 200 people (Youngblom E. et al. 1993 and Nordestgaard BG et al. 34:3478–3490a, 2013) and leading to significant risk for heart disease. Clinical genomics testing using high-throughput sequencing is identifying novel genomic variants of uncertain significance (VUS) in individuals suspected of having FH, but for whom the causal link to the disease remains to be established (Nordestgaard BG et al. 34:3478–3490a, 2013). Unfortunately, experimental data about the atomic structure of the LDL binding domains of LDLR at extracellular pH does not exist. This leads to an inability to apply protein structure-based methods for assessing novel variants identified through genetic testing. Thus, the ambiguities in interpretation of LDLR variants are a barrier to achieving the expected clinical value for personalized genomics assays for management of FH. In this study, we integrated data from the literature and related cellular receptors to develop high-resolution models of full-length LDLR at extracellular conditions and use them to predict which VUS alter LDL binding. We believe that the functional effects of LDLR variants can be resolved using a combination of structural bioinformatics and functional assays, leading to a better correlation with clinical presentation. We have completed modeling of LDLR in two major physiologic conditions, generating detailed hypotheses for how each of the 1007 reported protein variants may affect function. Key messages • Hundreds of variants are observed in the LDLR, but most lack interpretation. • Molecular modeling is aided by biochemical knowledge. • We generated context-specific 3D protein models of LDLR. • Our models allowed mechanistic interpretation of many variants. • We interpreted both rare and common genomic variants in their physiologic context. • Effects of genomic variants are often context-specific. Electronic supplementary material The online version of this article (10.1007/s00109-019-01755-3) contains supplementary material, which is available to authorized users.

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Novel de novo variant in EBF3 is likely to impact DNA binding in a patient with a neurodevelopmental disorder and expanded phenotypes: patient report, in silico functional assessment, and review of published cases

Cited by 23 publications

References 37 publications

De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism

De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism

An ancient role for Collier/Olf/Ebf (COE)-type transcription factors in axial motor neuron development

Molecular modeling of LDLR aids interpretation of genomic variants

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