Alternative titles; symbols
HGNC Approved Gene Symbol: CPAMD8
SNOMEDCT: 1197358003;
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38) : 19:16,892,951-17,026,810 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.11 | Anterior segment dysgenesis 8 | 617319 | Autosomal recessive | 3 |
CPAMD8 belongs to the complement component-3 (C3; 120700)/alpha-2-macroglobulin (A2M; 103950) family of proteins, which are involved in innate immunity and damage control. Complement components recognize and eliminate pathogens by direct binding or by mediating opsonization/phagocytosis and intracellular killing, and A2M is a broad-spectrum protease inhibitor (Li et al., 2004).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (1999) cloned CPAMD8, which they designated KIAA1283. The deduced 1,884-amino acid protein shares 35% identity with 643 C-terminal amino acids of A2M. RT-PCR ELISA detected moderate to high CPAMD8 expression in all tissues and brain regions examined. Highest expression was in spinal cord, and lowest was in pancreas.
By searching databases for sequences similar to C3/A2M proteins, followed by PCR, Li et al. (2004) cloned CPAMD8. The deduced 1,885-protein has an N-terminal signal peptide, a conserved RxxR furin (136950) processing site, a thioester motif, a conserved specificity-determining region, a C-terminal Kazal-type protease inhibitor domain, and a putative C-terminal prenylation motif. RT-PCR detected highest expression in kidney, brain, and testis, with lower expression in small intestine, liver, and heart, and no expression in lung, skeletal muscle, pancreas, and ovary. Western blot analysis detected highest amounts of CPAMD8 protein in kidney and in the cortical layer of brain. In vitro translated protein had an apparent molecular mass of 200 kD. Endogenous CPAMD8 was detected in several human cell lines, and it was proteolytically processed at the furin cleavage site into 2 chains of about 70 and 130 kD. Differential solubilization and cell attachment assays of HEK293 cells overexpressing CPAMD8 revealed that the protein was present on the cell surface.
Cheong et al. (2016) used RT-PCR to analyze the expression of the CPAMD8-1a and CPAMD8-1b isoforms in the developing human fetal eye. Both isoforms were detected in the developing lens and retina as early as week 9 of gestation, and expression was retained into the second trimester. Expression was also detected in the iris and cornea at week 22 of gestation. Differential temporal expression was observed in the lens and retina, with increasing levels of expression in the lens from early to later developmental stages, and decreasing levels of expression in the retina. In situ hybridization (ISH) confirmed the RT-PCR findings, showing robust CPAMD8 expression in the embryonic neural retina from the seventh to eighth week, whereas lower expression was detected in the embryonic lens. In addition, ISH revealed strong expression of CPAMD8 in the distal tips of the retinal neuroepithelium that contributes to the development of the iris and ciliary body by the eighth week. Cheong et al. (2016) noted that ISH did not detect significant embryonic expression of CPAMD8 in the periocular mesenchyme or in the mesenchyme anterior to the lens, corresponding to the pupillary membrane and developing cornea at Carnegie stage 23 (8 weeks postovulation), whereas CPAMD8 expression was readily detected by RT-PCR at later stages in the fetal lens, iris, and cornea.
Li et al. (2004) determined that the CPAMD8 gene contains 40 exons and spans about 130 kb.
By genomic sequence analysis, Li et al. (2004) mapped the CPAMD8 gene to chromosome 19p13.3-p13.2. The last 5 exons of CPAMD8 overlap the last exon of the PAR4 gene (601936) on the opposite strand.
Li et al. (2004) determined that the Kazal domain of CPAMD8 binds heparin, and subcellular fractionation showed that CPAMD8 is membrane associated via ionic interaction. In glioma and rhabdomyosarcoma cell lines, CPAMD8 expression was upregulated in response to immune stimulants.
In 4 affected individuals from 3 unrelated families with anterior segment dysgenesis-8 (ASGD8; 617319), Cheong et al. (2016) identified homozygous and compound heterozygous mutations in the CPAMD8 gene (see, e.g., 608841.0001-608841.0003) that segregated with disease in the families.
In a 24-year-old South Asian woman with anterior segment dysgenesis-8 (ASGD8; 617319), Cheong et al. (2016) identified homozygosity for a c.4351T-C transition (c.4351T-C, NM_015692.2) in exon 32 of the CPAMD8 gene, resulting in a ser1451-to-pro (S1451P) substitution at a highly conserved residue within the alpha-2-macroglobulin (A2M) complement component domain. Her unaffected first-cousin parents were heterozygous for the mutation, which was not found in an internal database (UCL-ex) or the 1000 Genomes Project, Exome Variant Server, or ExAC databases.
In a 17-year-old boy with anterior segment dysgenesis-8 (ASGD8; 617319), Cheong et al. (2016) identified compound heterozygosity for a 1-bp insertion (c.2352_2353insC, NM_015692.2) in exon 18 of the CPAMD8 gene, causing a frameshift predicted to result in a premature termination codon (Arg785GlnfsTer23), and a splice mutation (c.4549-1G-A; 608841.0003) in intron 33, predicted to disrupt normal splicing. In vitro splice assay with the mutant construct confirmed aberrant pre-mRNA splicing, with the production of 4 abnormal transcripts. The boy's father was heterozygous for the frameshift variant, but his mother's mutation status was unknown. Neither mutation was found in an internal database (UCL-ex) or the 1000 Genomes Project database. However, heterozygous frequencies in the Exome Variant Server and ExAC databases were 21/11,520 alleles and 47/115,670 alleles for the frameshift mutation, and 1/12,356 alleles and 1/120,688 alleles for the splice site mutation, respectively, consistent with predicted allele frequencies for a rare recessive disease. No homozygotes for these variants were present in any of the databases.
For discussion of the splice acceptor site mutation (c.4549-1G-A, NM_015692.2) in intron 33 of the CPAMD8 gene that was found in compound heterozygous state in a patient with anterior segment dysgenesis-8 (ASGD8; 617319) by Cheong et al. (2016), see 608841.0002.
Cheong, S.-S., Hentschel, L., Davidson, A. E., Gerrelli, D., Davie, R., Rizzo, R., Pontikos, N., Plagnol, V., Moore, A. T., Sowden, J. C., Michaelides, M., Snead, M., Tuft, S. J., Hardcastle, A. J. Mutations in CPAMD8 cause a unique form of autosomal-recessive anterior segment dysgenesis. Am. J. Hum. Genet. 99: 1338-1352, 2016. [PubMed: 27839872] [Full Text: https://doi.org/10.1016/j.ajhg.2016.09.022]
Li, Z.-F., Wu, X., Engvall, E. Identification and characterization of CPAMD8, a novel member of the complement 3/alpha-2-macroglobulin family with a C-terminal Kazal domain. Genomics 83: 1083-1093, 2004. [PubMed: 15177561] [Full Text: https://doi.org/10.1016/j.ygeno.2003.12.005]
Nagase, T., Ishikawa, K., Kikuno, R., Hirosawa, M., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 337-345, 1999. [PubMed: 10574462] [Full Text: https://doi.org/10.1093/dnares/6.5.337]