Alternative titles; symbols
HGNC Approved Gene Symbol: CAPZA2
Cytogenetic location: 7q31.2 Genomic coordinates (GRCh38): 7:116,862,587-116,922,049 (from NCBI)
The CAPZA2 gene encodes a subunit of an F-actin-capping protein complex (CapZ), which functions to arrest elongation of newly formed dynamic actin filaments (summary by Huang et al., 2020).
Barron-Casella et al. (1995) stated that CapZ was identified in chicken as a nonsevering, barbed-end actin-binding protein composed of alpha and beta subunits. In the chicken, 2 cDNAs were isolated for the alpha subunit. The alpha-1 (CAPZA1; 601580) and alpha-2 isoforms, which share 85% identity, are the products of 2 separate genes; 1 gene appears to be responsible for beta-subunit expression (CAPZB; 601572). By capping the barbed end of actin filaments, CapZ regulates the growth of the actin filament at the barbed end.
Barron-Casella et al. (1995) isolated human retinal cDNAs that are homologs of the alpha-2 and beta subunits of chicken CapZ. The derived human alpha-2 subunit shares 95% amino acid identity with the chicken alpha-2 subunit; the beta subunit is 99% identical to chicken subunit residues 1-243. The remaining portion of the human beta subunit (amino acids 244-272) diverges significantly with only 8 out of 29 C-terminal amino acids conserved between the 2 species.
Barron-Casella et al. (1995) mapped the CAPZA2 gene to chromosome 7q31.2-q31.3 by PCR screening of the NIGMS human/rodent somatic cell hybrid mapping panel 2, with refinement by PCR analysis of a human chromosome 7-specific YAC library. One set of overlapping clones contained both the MET gene (164860) and the CAPZA2 gene. The 2 genes were separated by a maximum distance of 330 kb, with MET centromeric and WNT2 (147870) and CFTR (602421) distal to CAPZA2.
Hart et al. (1997) cloned the mouse homolog of the CAPZA2 gene. By interspecific backcross analysis, they mapped the mouse Capza2 gene to chromosome 6, in a region that shows conservation of synteny with human 7q31.2-q31.3.
Associations Pending Confirmation
For discussion of a possible association between variation in the CAPZA2 gene and an intellectual developmental disorder, see 601571.0001 and 601571.0002.
This variant is classified as a variant of unknown significance because its contribution to an intellectual developmental disorder has not been confirmed.
In a 2.5-year-old Chinese girl (patient 1) with an intellectual developmental disorder, Huang et al. (2020) identified a de novo heterozygous c.776G-T transversion (chr7.116,557,836G-T) in the CAPZA2 gene, resulting in an arg259-to-leu (R259L) substitution at a conserved residue. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the R259L variant was able to partially rescue lethality of Drosophila with biallelic null mutations in the orthologous cpa gene, suggesting that the variant causes a partial loss of function. Additional studies in cpa mutant Drosophila indicated that the variant caused mild morphologic defects in neurosensory bristles associated with disrupted F-actin organization, with a dominant-negative effect. The girl, who was conceived by in vitro fertilization and had an unaffected fraternal twin sister, had feeding difficulties and hypotonia soon after birth. She developed seizures and infantile spasms in the first year of life. EEG showed hypsarrhythmia initially, but was later normal. Brain imaging was normal. At age 2, she was able to sit and to utter some syllables.
This variant is classified as a variant of unknown significance because its contribution to an intellectual developmental disorder has not been confirmed.
In a 9-year-old girl of European descent (patient 2) with an intellectual developmental disorder, Huang et al. (2020) identified a de novo heterozygous c.766A-G transition (chr7.11,657,826A-G) in the CAPZA2 gene, resulting in a lys256-to-glu (K256E) substitution at a conserved residue. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the K256E variant was able to partially rescue lethality of Drosophila with biallelic null mutations in the orthologous cpa gene, suggesting that the variant causes a partial loss of function. Overexpression of K256E in wildtype Drosophila caused a mild morphologic defect in a subset of neurosensory bristles. Additional studies in cpa mutant Drosophila suggested that the variant caused severe bristle defects associated with disrupted F-actin organization, with a dominant-negative effect. The patient had hypotonia and poor feeding in infancy, and later showed global developmental delay with severely impaired intellectual development. She walked with an abnormal gait at age 3 years, had limited speech, and was diagnosed with autism spectrum disorder. She had a single atypical febrile seizure that was controlled with medication. Brain imaging showed mild myelination defects.
Barron-Casella, E. A., Torres, M. A., Scherer, S. W., Heng, H. H. Q., Tsui, L.-C., Casella, J. F. Sequence analysis and chromosomal localization of human Cap Z: conserved residues within the actin-binding domain may link Cap Z to gelsolin/severin and profilin protein families. J. Biol. Chem. 270: 21472-21479, 1995. [PubMed: 7665558] [Full Text: https://doi.org/10.1074/jbc.270.37.21472]
Hart, M. C., Korshunova, Y. O., Cooper, J. A. Mapping of the mouse actin capping protein alpha subunit genes and pseudogenes. Genomics 39: 264-270, 1997. [PubMed: 9119363] [Full Text: https://doi.org/10.1006/geno.1996.4506]
Huang, Y., Mao, X., van Jaarsveld, R. H., Shu, L., Terhal, P. A., Jia, Z., Xi, H., Peng, Y., Yan, H., Yuan, S., Li, Q., Wang, H., Bellen, H. J. Variants in CAPZA2, a member of an F-actin capping complex, cause intellectual disability and developmental delay. Hum. Molec. Genet. 29: 1537-1546, 2020. [PubMed: 32338762] [Full Text: https://doi.org/10.1093/hmg/ddaa078]