YWHAZ variation causes intellectual disability and global developmental delay with brain malformation

Abstract

YWHAZ encodes an adapter protein 14–3-3ζ, which is involved in many signaling pathways that control cellular proliferation, migration, and differentiation. It has not been definitely correlated to any phenotype in OMIM. To investigate the role of YWHAZ gene in intellectual disability and global developmental delay, we conducted whole-exon sequencing in all of available members from a large three-generation family and we discovered that a novel variant of the YWHAZ gene was associated with intellectual disability and global developmental delay. This variant is a missense mutation of YWHAZ, p.Lys49Asn/c.147A > T, which was found in all affected members but not found in other unaffected members. We also conducted computational modeling and knockdown/knockin with Drosophila to confirm the role of the YWHAZ variant in intellectual disability. Computational modeling showed that the binding energy was increased in the mutated protein combining with the ligand indicating that the c147A > T variation was a loss-of-function variant. Cognitive defects and mushroom body morphological abnormalities were observed in YWHAZ c.147A > T knockin flies. The YWHAZ knockdown flies also manifested serious cognitive defects with hyperactivity behaviors, which is consistent with the clinical features. Our clinical and experimental results consistently suggested that YWHAZ was a novel intellectual disability pathogenic gene.

Comprehensive Assessment of Ischemic Stroke in Nonhuman Primates: Neuroimaging, Behavioral, and Serum Proteomic Analysis

“…YWHAZ, part of the 14–3–3 protein family, affects cellular proliferation, migration, and differentiation by interacting with phosphoserine- and serine-containing proteins . Clinically, elevated levels of YWHAZ poststroke have been associated with cognitive impairment, while experimental models demonstrate that reduced YWHAZ expression leads to neurodevelopmental and cognitive deficits . Our study establishes the significance of five proteins in ischemic stroke, highlighting their potential as biomarkers and therapeutic targets.…”

Efficient strategies based on behavioral and electrophysiological methods for epilepsy-related gene screening in the Drosophila model

“…Knockdown of Tango14 results in hyperactive seizure behavior ( Figure 1 ), while knockdown of Klp3A results in late-phase seizure behavior ( Figure 2 ). Our findings were further validated by the demonstration of hyperactivity seizure behavior in knockdown of the Ywhaz gene ( Wan et al, 2022 ), suggesting that this novel behavior could be applied to verifying other epilepsy candidate genes. These results imply that loss of function in different candidate genes can result in distinct phenotypes.…”

“…These regions, namely, the mushroom body and central complex ( Figure 3 ), play a crucial role in higher-order cognitive functions. Our previous research has found that knockdown/knockout of genes involved in epilepsy or neural disorder, such as UNC13B , LRP1 , and YWHAZ , leads to various brain abnormalities, including neuron blurring in mushroom body ( Wang et al, 2021 ), partial destruction in the central complex ( Zhang et al, 2022 ), and gamma lobe mutilation in the mushroom body ( Wan et al, 2022 ). Although not all epilepsy gene defects could induce brain structural abnormalities, the morphological study still can provide valuable insights into the underlying mechanisms of epilepsy caused by specific genes.…”

“…For example, hundreds of missense mutations, including GOF mutations, in the gene SCN1A can confer a wide spectrum of epileptic phenotypes in Drosophila as they do in humans ( Schutte et al, 2014 ), thus knock-in Drosophila lines mimicking the missense variants should be generated to realize more precise genetic editing ( Xue et al, 2014 ). In our previous study, c.147A > T missense variation of Ywhaz was created using the CRISPR/Cas9 system to confirm its pathogenic effects ( Wan et al, 2022 ). Thus, the knockdown model established by the Gal4/UAS system and the knock-in model established by the CRISPR/Cas9 system can cover most scenarios of gene mutations, including LOF and GOF mutations.…”

Comprehensive Assessment of Ischemic Stroke in Nonhuman Primates: Neuroimaging, Behavioral, and Serum Proteomic Analysis

“…YWHAZ, part of the 14-3-3 protein family, affects cellular proliferation, migration, and differentiation by interacting with phosphoserine-and serine-containing proteins (Aghazadeh & Papadopoulos, 2016). Clinically, elevated levels of YWHAZ post-stroke have been associated with cognitive impairment (Qi et al, 2023), while experimental models demonstrate that reduced YWHAZ expression leads to neurodevelopmental and cognitive deficits (Wan et al, 2023). Our study establishes the significance of five proteins in in ischemic stroke, highlighting their potential as biomarkers and therapeutic targets.…”