YWHAZ was initially proposed as an autism candidate gene based on the discovery of a frameshift variant in this gene in both ASD-affected siblings from a multiplex family (Toma et al., 2014); this variant was subsequently reported in Torrico et al., 2020 to have been inherited from a mother with depression and to result in reduced solubility, a loss in the ability to bind Ser19-phosphorylated tyrosine hydroxylase, and a loss in the ability to form heterodimers with 14-3-3. Additional de novo variants in this gene have been identified in ASD probands, including a rare and potentially deleterious missense variant in a proband from the Autism Sequencing Consortium (Sanders et al., 2015; Yuen et al., 2017; Turner et al., 2017; Satterstrom et al., 2020). Torrico et al., 2020 reported reduced expression of YWHAZ in the cerebellum of ASD cases compared to controls. Popov et al., 2019 reported YWHAZ variants in five individuals presenting with neurodevelopmental phenotypes; one of these individuals presented with autism, while another presented with autistic behavior. YWHAZ has also been proposed as a schizophrenia candidate gene based on genetic association studies, the enrichment of ultra-rare variants in schizophrenia cases, and reduced expression in post-mortem brain tissue from schizophrenia patients (Jia et al., 2004; Middleton et al., 2005; Sun et al., 2011; Fromer et al., 2014; Torrico et al., 2020). Deficiency of YWHAZ in both mice and zebrafish has been shown to result in anatomical and behavioral defects that mirror human phenotypes (Cheah et al., 2015; Xu et al., 2015; Anton-Galindo et al., 2022).
Molecular Function
This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 99% identical to the mouse, rat and sheep orthologs. The encoded protein interacts with IRS1 protein, suggesting a role in regulating insulin sensitivity. In neurons, this protein regulates spine maturation through the modulation of ARHGEF7 activity.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.
Application of systems biology approach identifies and validates GRB2 as a risk gene for schizophrenia in the Irish Case Control Study of Schizophrenia (ICCSS) sample
An association study between polymorphisms in three genes of 14-3-3 (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein) family and paranoid schizophrenia in northern Chinese popul
