Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism.
Am J Hum Genet
; 100(1): 117-127, 2017 Jan 05.
Article
en En
| MEDLINE
| ID: mdl-28017373
ABSTRACT
From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in â¼0.1% of individuals with unexplained neurodevelopmental disorders.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Ataxia
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Factores de Transcripción
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Transcripción Genética
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Cara
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Trastornos del Neurodesarrollo
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Trastornos del Desarrollo del Lenguaje
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Discapacidad Intelectual
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Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Adolescent
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Adult
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Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Am J Hum Genet
Año:
2017
Tipo del documento:
Article
País de afiliación:
Alemania