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Summary The translation initiation repressor 4E-BP2 is deamidated in the brain on asparagines N99/N102 during early postnatal brain development. This post-translational modification enhances 4E-BP2 association with Raptor, a central component of mTORC1 and alters the kinetics of excitatory synaptic transmission. We show that 4E-BP2 deamidation is neuron specific, occurs in the human brain, and changes 4E-BP2 subcellular localization, but not its disordered structure state. We demonstrate that deamidated 4E-BP2 is ubiquitinated more and degrades faster than the unmodified protein. We find that enhanced deamidated 4E-BP2 degradation is dependent on Raptor binding, concomitant with increased association with a Raptor-CUL4B E3 ubiquitin ligase complex. Deamidated 4E-BP2 stability is promoted by inhibiting mTORC1 or glutamate receptors. We further demonstrate that deamidated 4E-BP2 regulates the translation of a distinct pool of mRNAs linked to cerebral development, mitochondria, and NF-κB activity, and thus may be crucial for postnatal brain development in neurodevelopmental disorders, such as ASD.

For many patients with complex diseases the time from onset of symptoms to diagnosis may involve many years. If a diagnosis can be reached, it often comes at great financial and emotional cost. With the advent of sequencing technologies, the ability to identify gene variants has increased exponentially. Interpreting these findings, however, remains challenging. The purpose of this study was to analyze a mutation in the CUL4B gene revealed by whole exome sequencing (WES) in a patient with seizures and developmental delay. Recognizing that complex disease may involve the interaction of many genes and their protein products, an analysis of variants in selected CUL4B associated proteins and CUL4A was also undertaken with the ultimate goal of determining their potential clinical relevancy. WES was performed by Ambry Genetics and mRNA studies were performed by University of California CLIA laboratory MitoMed. WES identified a variant in CUL4B located on the X chromosome. Analysis revealed a splice site mutation resulting in skipping of exon 14 or inclusion of intron 14. Examination of the biological structure indicated that in either case no functional protein would be found. Fifteen intronic variants and one synonymous exonic variant were identified in CUL4B related genes. Fourteen intronic variants in CUL4A were also identified. Current understanding of these types of variants suggests they would not be contributory, however further study is required. Taken together, these results contribute to the growing body of evidence that mutations in the CUL4B gene may be causal in cases of X linked intellectual disability.

For many patients with complex diseases the time from onset of symptoms to diagnosis may involve many years. If a diagnosis can be reached, it often comes at great financial and emotional cost. With the advent of sequencing technologies, the ability to identify gene variants has increased exponentially. Interpreting these findings, however, remains challenging. The purpose of this study was to analyze a mutation in the CUL4B gene revealed by whole exome sequencing (WES) in a patient with seizures and developmental delay. Recognizing that complex disease may involve the interaction of many genes and their protein products, an analysis of variants in selected CUL4B associated proteins and CUL4A was also undertaken with the ultimate goal of determining their potential clinical relevancy. WES was performed by Ambry Genetics and mRNA studies were performed by University of California CLIA laboratory MitoMed. WES identified a variant in CUL4B located on the X chromosome. Analysis revealed a splice site mutation resulting in skipping of exon 14 or inclusion of intron 14. Examination of the biological structure indicated that in either case no functional protein would be found. Fifteen intronic variants and one synonymous exonic variant were identified in CUL4B related genes. Fourteen intronic variants in CUL4A were also identified. Current understanding of these types of variants suggests they would not be contributory, however further study is required. Taken together, these results contribute to the growing body of evidence that mutations in the CUL4B gene may be causal in cases of X linked intellectual disability.

Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.