Alternative titles; symbols
HGNC Approved Gene Symbol: AGR2
Cytogenetic location: 7p21.1 Genomic coordinates (GRCh38) : 7:16,791,811-16,804,999 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p21.1 | Respiratory infections, recurrent, and failure to thrive with or without diarrhea | 620233 | Autosomal recessive | 3 |
The AGR2 protein plays an important role in mucus production and in homeostasis of the respiratory and intestinal tracts (Bertoli-Avella et al., 2022).
Estrogen receptor (ER; 133430)-negative breast cancers are less well-differentiated and more aggressive than ER-positive tumors. Using suppression subtractive hybridization, Kuang et al. (1998) identified 29 gene fragments expressed in ER-positive breast carcinomas that might contribute to its less aggressive phenotype compared to ER-negative tumors. The expression of one of these fragments, DEME2, correlated with ER expression in 8 breast carcinoma cell lines. By screening an ER-positive breast cancer cDNA library with the DEKE2 fragment, followed by EST database searching, Thompson and Weigel (1998) obtained a cDNA encoding AGR2, a homolog of the frog secreted cement gland anterior gradient protein, which they termed AG2. The deduced 175-amino acid soluble AGR2 protein, which is 91% identical to the mouse protein and 47% identical to the frog protein, contains a signal peptide. Northern blot analysis revealed strongest expression of 0.9- and 1.6-kb AGR2 transcripts in lung and in all ER-positive breast carcinoma lines tested; weaker expression was detected in pancreas. RNA dot blot analysis detected strong expression in trachea, lung, stomach, colon, prostate, and small intestine, with lower expression in other tissues.
Bertoli-Avella et al. (2022) stated that the AGR2 protein is expressed at high levels in tissues that secrete mucus or function as endocrine organs, including respiratory tract, stomach, colon, prostate, and small intestine. AGR2 localizes to the lumen of the endoplasmic reticulum.
By radiation hybrid analysis and FISH, Petek et al. (2000) mapped the AGR2 gene to 7p21.3.
Fletcher et al. (2003) determined that the AG2 gene contains 7 exons and spans about 26 kb.
By immunohistochemical and real-time quantitative RT-PCR analyses, Fletcher et al. (2003) found that AG2 and AG3 (609482) mRNA and protein exhibited similar expression patterns in breast cancer tissues. Expression of AG2 and AG3 showed a positive correlation with expression of estrogen receptor and a negative correlation with expression of EGF receptor (EGFR; 131550). Yeast 2-hybrid analysis identified C4.4A (609484) and extracellular alpha-dystroglycan (DAG1; 128239) as binding partners for both AG2 and AG3.
In an Omani girl and 2 female cousins (family 1) with recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD; 620233), Bertoli-Avella et al. (2022) identified homozygosity for a missense mutation in the AGR2 gene (P71T; 606358.0001) that segregated fully with disease. Investigation of exome or genome data from 39,756 patients with an overlapping phenotype in an in-house bioinformatics database yielded 10 additional patients from 8 families with very similar phenotypic features and homozygous mutations in AGR2i (see, e.g., 606358.0002-606358.0004). Where DNA was available, the mutations were shown to segregate fully with disease in the families, and were either not found or were present at very low minor allele frequency in the gnomAD database.
Kumar et al. (2007) found that in the adult salamander, limb regeneration is dependent upon the surface protein Prod1, whose human homolog is CD59 (107271), as a critical determinant of proximodistal identity. The anterior gradient protein family member newt AG, whose human homolog is AG2, is a secreted ligand for Prod1 and a growth factor for cultured newt blastemal cells. Newt AG is sequentially expressed after amputation in the regenerating nerve and the wound epidermis--the key tissues of the stem cell niche--and its expression in both locations is abrogated by denervation. The local expression of newt AG after electroporation is sufficient to rescue a denervated blastema and regenerate the distal structures. Kumar et al. (2007) concluded that their analysis brought together the positional identity of the blastema and the classical nerve dependence of limb regeneration.
In an Omani girl and 2 female cousins (family 1) with recurrent respiratory infections and failure to thrive (RIFTD; 620233), Bertoli-Avella et al. (2022) identified homozygosity for a c.211C-A transversion (c.211C-A, NM_006408.3) in exon 4 of the AGR2 gene, resulting in a pro71-to-thr (P71T) substitution. The proband's unaffected first-cousin parents were heterozygous for the substitution, which was not found in the gnomAD database.
In 4 children from 3 Syrian families (families 2, 4, and 7) and 1 from an Iraqi family (family 3) with recurrent respiratory infections and failure to thrive with or without chronic diarrhea (RIFTD; 620233), Bertoli-Avella et al. (2022) identified homozygosity for a c.349C-T transition (c.349C-T, NM_006408.3) in exon 6 of the AGR2 gene, resulting in a his117-to-tyr (H117Y) substitution. The unaffected parents in the 3 families for which DNA was available were heterozygous for the variant, which was present at very low minor allele frequency in the gnomAD database (1/250,930 alleles). The 4 families shared a haplotype around AGR2, suggesting a common ancestor, with the 3 families of Syrian origin showing a larger shared chromosome region of approximately 8.2 Mb.
In an Egyptian sister and brother (family 5) with recurrent respiratory infections and failure to thrive with or without chronic diarrhea (RIFTD; 620233), Bertoli-Avella et al. (2022) identified homozygosity for a splice site variant (c.330+1G-T, NM_006408.3) in intron 5 of the AGR2 gene, predicted to abolish normal splicing. Their consanguineous parents were heterozygous for the variant, which was present at very low minor allele frequency in the gnomAD database (1/249,340 alleles). Both sibs exhibited hepatomegaly; only the brother had vomiting and chronic diarrhea.
In a Pakistani boy (family 9) with recurrent respiratory infections and failure to thrive with chronic diarrhea (RIFTD; 620233), Bertoli-Avella et al. (2022) identified homozygosity for a c.428G-A transition (c.428G-A, NM_006408.3) in exon 7 of the AGR2 gene, resulting in a gly143-to-glu (G143E) substitution at a conserved residue. His unaffected consanguineous parents were heterozygous for the variant, which was not found in the gnomAD database.
Bertoli-Avella, A., Hotakainen, R., Al Shehhi, M., Urzi, A., Pareira, C., Marais, A., Al Shidhani, K., Aloraimi, S., Morales-Torres, G., Fisher, S., Demuth, L., Moteleb Selim, L. A., and 27 others. A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene. J. Med. Genet. 59: 993-1001, 2022. [PubMed: 34952832] [Full Text: https://doi.org/10.1136/jmedgenet-2021-108150]
Fletcher, G. C., Patel, S., Tyson, K., Adam, P. J., Schenker, M., Loader, J. A., Daviet, L., Legrain, P., Parekh, R., Harris, A. L., Terrett, J. A. hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan. Brit. J. Cancer 88: 579-585, 2003. [PubMed: 12592373] [Full Text: https://doi.org/10.1038/sj.bjc.6600740]
Kuang, W. W., Thompson, D. A., Hoch, R. V., Weigel, R. J. Differential screening and suppression subtractive hybridization identified genes differentially expressed in an estrogen receptor-positive breast carcinoma cell line. Nucleic Acids Res. 26: 1116-1123, 1998. [PubMed: 9461476] [Full Text: https://doi.org/10.1093/nar/26.4.1116]
Kumar, A., Godwin, J. W., Gates, P. B., Garza-Garcia, A. A., Brockes, J. P. Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science 318: 772-777, 2007. [PubMed: 17975060] [Full Text: https://doi.org/10.1126/science.1147710]
Petek, E., Windpassinger, C., Egger, H., Kroisel, P. M., Wagner, K. Localization of the human anterior gradient-2 gene (AGR2) to chromosome band 7p21.3 by radiation hybrid mapping and fluorescence in situ hybridisation. Cytogenet. Cell Genet. 89: 141-142, 2000. [PubMed: 10965104] [Full Text: https://doi.org/10.1159/000015594]
Thompson, D. A., Weigel, R. J. hAG-2, the human homologue of the Xenopus laevis cement gland gene XAG-2, is coexpressed with estrogen receptor in breast cancer cell lines. Biochem. Biophys. Res. Commun. 251: 111-116, 1998. [PubMed: 9790916] [Full Text: https://doi.org/10.1006/bbrc.1998.9440]