• developmental disorder of mental health

This report describes global developmental delay with impaired intellectual development, hypotonia, and seizures, CAPZA2-related, which can be described as a syndromic form of intellectual disability. Two de novo mutations of CAPZA2 implicated in this disease have been described. CAPZA2 encodes a member of the F-actin capping protein alpha subunit family. There is a single orthologous gene in Drosophila, cpa, for which loss-of-function alleles, RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated. Dmel\cpa is orthologous to two additional human genes, CAPZA1 and CAPZA3.

Multiple UAS constructs of the human Hsap\CAPZA2 have been introduced into flies, including wild-type and variants implicated in this disease. Heterologous rescue (functional complementation) has been demonstrated for the lethal phenotype of Dmel\cpa loss-of-function mutations.

Variant(s) implicated in human disease tested (as transgenic human gene, CAPZA2): the K256E and R259L variant forms of the human gene have been introduced into flies. Rescue by the variants forms is observed, but is less robust than with wild-type. This suggests that both variants are mild loss-of-function forms; in addition, they both have a mild dominant negative effect on bristle morphogenesis.

Animals homozygous for null alleles of Dmel\cpa typically die in the first larval instar stage. Use of somatic clones and RNAi-mediated knockdown in specific tissues have provided insights into the roles of cpa in the development of imaginal discs, in maintenance of epithelial integrity, in oogenesis, and in maintaining neuronal homeostasis. Physical and genetic interactions of cpa have been described; see below and in the cpa gene report.

[updated Jul. 2020 by FlyBase; FBrf0222196]