Alternative titles; symbols
HGNC Approved Gene Symbol: BCAS3
Cytogenetic location: 17q23.2 Genomic coordinates (GRCh38) : 17:60,677,851-61,392,831 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.2 | Hengel-Maroofian-Schols syndrome | 619641 | Autosomal recessive | 3 |
The BCAS3 gene encodes a large, highly conserved cytoskeletal protein involved in human embryogenesis and tumorigenesis by regulating endothelial migration and angiogenesis (summary by Hengel et al., 2021).
Using a cDNA microarray-based analysis of genes amplified in breast cancer cell lines, Barlund et al. (2002) identified BCAS3. They obtained the full-length sequence from a liver cDNA library using several cloning techniques. The deduced 913-amino acid protein has a calculated molecular mass of 99 kD. Northern blot analysis revealed a 3.9-kb transcript expressed in all tissues examined. Several smaller transcripts showed tissue-specific distribution. Multiple tissue expression array analysis indicated ubiquitous expression, with highest levels in stomach, liver, lung, kidney, fetal kidney, prostate, testis, thyroid gland, and adrenal gland.
Using a functional genomic screen, Gururaj et al. (2006) identified BCAS3 as a chromatin target of MTA1 (603526). MTA1 stimulation of BCAS3 transcription required estrogen receptor-1 (ESR1; 133430) and involved a functional estrogen response element half-site in BCAS3. Furthermore, MTA1 was acetylated on lys626, and this acetylation was necessary for productive transcriptional recruitment of RNA polymerase II complex to the BCAS3 enhancer sequence. BCAS3 expression was elevated in mammary tumors from MTA1 transgenic mice and in 60% of human breast tumors, and it correlated with coexpression of MTA1 as well as with tumor grade and proliferation of primary breast tumor cultures.
Barlund et al. (2002) determined that the BCAS3 gene contains 24 exons and spans more than 600 kb, including an intron of nearly 300 kb between exons 22 and 23.
By genomic sequence analysis, Barlund et al. (2002) mapped the BCAS3 gene to chromosome 17q23.
Barlund et al. (2002) determined that a 1.3-kb transcript overexpressed in the MCF7 breast carcinoma cell line resulted from a fusion between the BCAS3 gene from chromosome 17 and the BCAS4 gene (607471) from chromosome 20. Although amplification of either or both genes was common in the 12 other breast cancer cell lines examined, no other cell line expressed the fusion transcript.
In 15 patients from 8 unrelated families with Hengel-Maroofian-Schols syndrome (HEMARS; 619641), Hengel et al. (2021) identified homozygous or compound heterozygous mutations in the BCAS3 gene (see, e.g., 607470.0001-607470.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were nonsense, missense, frameshift, and splice site mutations that occurred throughout the gene. All mutations were either absent from or present at a low frequency in the gnomAD database (v.2.1.1 or v.3). Studies of fibroblasts derived from 2 unrelated patients showed undetectable BCAS3 protein levels compared to controls, suggesting a loss-of-function effect. Patient fibroblasts did not show cell migration abnormalities and the patients did not have angiogenesis defects. The findings suggested an essential role for BCAS3 in neurodevelopment.
Hengel et al. (2021) noted that homozygous loss of the Bcas3 gene in mice is embryonic lethal. They found that RNAi-mediated knockdown of the corresponding Drosophila 'rudhira' gene by use of panneuronal drivers in Drosophila also caused embryonic lethality or paralyzed flies that died on the first day after eclosion. Further genetic studies of mutant flies showed that loss of rudhira reduced longevity and caused severe locomotion defects and an abnormal wing phenotype. Overall, the findings indicated that knockdown of this gene can cause developmental defects in neuronal and nonneuronal tissues in a dose-dependent manner.
In 2 sibs, born of consanguineous Iranian parents (family 1), with Hengel-Maroofian-Schols syndrome (HEMARS; 619641), Hengel et al. (2021) identified a homozygous c.73C-T transition (c.73C-T, NM_001099432.3) in the BCAS3 gene, resulting in a gln25-to-ter (Q25X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In 3 sibs, born of consanguineous Arab Palestinian parents (family 2), with Hengel-Maroofian-Schols syndrome (HEMARS; 619641), Hengel et al. (2021) identified a homozygous c.726T-G transversion (c.726T-G, NM_001099432.3) in the BCAS3 gene, resulting in a tyr242-to-ter (Y242X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In 2 sisters, born of consanguineous parents of European descent (family 3), with Hengel-Maroofian-Schols syndrome (HEMARS; 619641), Hengel et al. (2021) identified a homozygous c.1457C-G transversion (c.1457C-G, NM_001099432.3) in the BCAS3 gene, resulting in a ser486-to-ter (S486X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Patient fibroblasts showed decreased BCAS3 mRNA levels, suggesting nonsense-mediated mRNA decay, and undetectable levels of BCAS3 protein compared to controls. The findings were consistent with a loss-of-function effect. Patient fibroblasts did not show cell migration defects.
In a boy, born of unrelated Albanian parents (family 4), with Hengel-Maroofian-Schols syndrome (HEMARS; 619641), Hengel et al. (2021) identified compound heterozygous missense mutations in the BCAS3 gene: a c.1700C-T transition (c.1700C-T, NM_001099432.3), resulting in a pro567-to-leu (P567L) substitution, and a c.1729G-A transition, resulting in a gly577-to-arg (G577R; 607470.0005) substitution. Both mutations occurred at highly conserved residues. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both were present at low frequencies in heterozygous state in the gnomAD database (less than 2.03 x 10(-5)). Patient fibroblasts showed undetectable levels of BCAS3 compared to controls, suggesting that the missense mutations cause a misfolded or unstable protein. The findings were consistent with a loss-of-function effect. Patient fibroblasts did not show cell migration defects.
For discussion of the c.1729G-A transition (c.1729G-A, NM_001099432.3) in the BCAS3 gene, resulting in a gly577-to-arg (G577R) substitution, that was found in compound heterozygous state in a patient with Hengel-Maroofian-Schols syndrome (HEMARS; 619641) by Hengel et al. (2021), see 607470.0004.
Barlund, M., Monni, O., Weaver, J. D., Kauraniemi, P., Sauter, G., Heiskanen, M., Kallioniemi, O.-P., Kallioniemi, A. Cloning of BCAS3 (17q23) and BCAS4 (20q13) genes that undergo amplification, overexpression, and fusion in breast cancer. Genes Chromosomes Cancer 35: 311-317, 2002. [PubMed: 12378525] [Full Text: https://doi.org/10.1002/gcc.10121]
Gururaj, A. E., Singh, R. R., Rayala, S. K., Holm, C., den Hollander, P., Zhang, H., Balasenthil, S., Talukder, A. H., Landberg, G., Kumar, R. MTA1, a transcriptional activator of breast cancer amplified sequence 3. Proc. Nat. Acad. Sci. 103: 6670-6675, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 110: 4147 only, 2013. [PubMed: 16617102] [Full Text: https://doi.org/10.1073/pnas.0601989103]
Hengel, H., Hannan, S. B., Dyack S., MacKay, S. B., Schatz, U., Fleger, M., Kurringer, A., Balousha, G., Ghanim, Z., Alkuraya, F. S., Alzaidan, H., Alsaif, H. S., and 36 others. Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder. Am. J. Hum. Genet. 108: 1069-1082, 2021. [PubMed: 34022130] [Full Text: https://doi.org/10.1016/j.ajhg.2021.04.024]