CAPZA2, encoding the α2 subunit of CAPZA, is crucial for actin polymerization and depolymerization in humans. The actin cytoskeleton, regulated by many proteins including capping proteins like CapZ (an obligate heterodimer with CAPZA2 as one subunit), is involved in various cellular processes [1,2].

Heterozygous CAPZA2 mutations have been found to cause global developmental delay, hypotonia, epilepsy, and other neurodevelopmental abnormalities such as delayed motor development, speech delay, intellectual disability, and a history of seizures in pediatric probands [1,2]. In a study, a novel de novo splicing variant in CAPZA2 led to exon 4 skipping in mRNA splicing, expanding the understanding of the phenotypic range associated with CAPZA2 deficiency and its mutational spectrum [1]. The identified CAPZA2 variants in probands also showed reduced efficiency in rescuing lethality in Drosophila, affecting bristle morphogenesis which requires extensive actin polymerization [2].

In conclusion, CAPZA2 is essential for regulating actin-related cellular processes. Research on CAPZA2, especially through studying its mutations in patients, has enhanced our understanding of non-syndromic neurodevelopmental disorders associated with it, highlighting its significance in neurodevelopmental biology and disease research.

References:

1. Zhang, Xiao-Man, Xu, Kai-Li, Kong, Jing-Hui, Gu, Wei-Yue, Mei, Shi-Yue. 2024. Heterozygous CAPZA2 mutations cause global developmental delay, hypotonia with epilepsy: a case report and the literature review. In Journal of human genetics, 69, 197-203. doi:10.1038/s10038-024-01230-z. https://pubmed.ncbi.nlm.nih.gov/38374166/

2. Huang, Yan, Mao, Xiao, van Jaarsveld, Richard H, Wang, Hua, Bellen, Hugo J. . Variants in CAPZA2, a member of an F-actin capping complex, cause intellectual disability and developmental delay. In Human molecular genetics, 29, 1537-1546. doi:10.1093/hmg/ddaa078. https://pubmed.ncbi.nlm.nih.gov/32338762/