Alternative titles; symbols
HGNC Approved Gene Symbol: ANG
SNOMEDCT: 1204351003;
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38): 14:20,684,177-20,694,186 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q11.2 | Amyotrophic lateral sclerosis 9 | 611895 | 3 |
The ANG gene encodes angiogenin, a 14.1-kD protein that is a potent inducer of neovascularization in vivo. ANG is a member of the pancreatic ribonuclease A superfamily, and RNase activity of ANG is important for its angiogenic activity. ANG is expressed in the neuroaxis. Endogenous ANG is required for cell proliferation induced by other angiogenic proteins such as vascular endothelial growth factor (VEGF; 192240). Like VEGF, ANG is induced by hypoxia to elicit angiogenesis and is expressed in motor neurons (Lambrechts et al., 2003).
Angiogenin was isolated from growth medium conditioned by human colon cancer cells. Rybak et al. (1987) demonstrated that angiogenin mRNA is expressed in a wide spectrum of cells and is not correlated to a particular cell phenotype.
Strydom et al. (1985) determined the complete amino acid sequence of angiogenin, and Kurachi et al. (1985) determined the nucleotide sequence of the ANG gene.
Angiogenin is a homolog of pancreatic ribonuclease (RNASE1; 180440) which, like angiogenin, is encoded by a gene on chromosome 14. As an initial step toward investigating the in vivo functional role of angiogenin via gene disruption, Brown et al. (1995) isolated the Ang gene from mouse strain 129. Unexpectedly, screening of a genomic library with an Ang gene probe obtained previously from the BALB/c strain yielded not Ang itself but 2 new genes closely similar to Ang. One of the genes encodes a protein with 78% sequence identity to angiogenin and was designated Angrp for 'angiogenin-related protein.' The ribonucleolytic active site of angiogenin, which is critical for angiogenic activity, was completely conserved in Angrp, whereas a second essential site, thought to bind cellular receptors, was considerably different. Thus, the Angrp product may have a function distinct from that of angiogenin. The second gene was a pseudogene that contained a frameshift mutation in the early part of the coding region. Although the Ang gene was not isolated from the BALB/c library, it was possible to amplify this gene from a strain 129 mouse genomic DNA by PCR. Sequence analysis showed that the strain 129 Ang gene is identical to the BALB/c gene throughout the coding region.
Wu et al. (2007) found strong ANG expression in the nucleus and cytoplasm of spinal cord ventral horn neurons of both human fetal and adult tissue specimens. ANG expression was detected in the extracellular matrix and interstitial tissue, consistent with it being a secreted protein, and ANG localized to spinal cord endothelial cells, suggesting a role in angiogenesis.
Hooper et al. (2003) reviewed the evidence that angiogenins are involved in host defense and noted that inflammation provokes upregulated ANG mRNA expression in liver and an increase in detectable ANG protein in serum. Unlike the single ANG gene found in humans, other primates, and rats, there are 2 genes in cattle and 4 in mice. The expression of mouse Ang4, produced by Paneth cells, is regulated by components of the normal murine intestinal flora. All the Ang proteins are derived from precursors with approximately 145 amino acids. Mature Ang4, Ang1, and ANG contain 120, 121, and 123 residues, respectively. Unlike Ang4, mouse Ang1 and human ANG, which share 77% amino acid identity, lack bactericidal activity against Enterococcus faecalis or Listeria monocytogenes. However, Ang1 and ANG, but not Ang4, have potent activity against Candida albicans and Streptococcus pneumoniae at concentrations comparable to those found in serum. Hooper et al. (2003) concluded that ANG is an important systemic antimicrobial protein.
Using yeast 2-hybrid and in vitro protein-binding assays, Gao et al. (2007) showed that follistatin (FST; 136470) bound ANG. When expressed individually, fluorescence-tagged FST and ANG showed diffuse nuclear localization in transfected HeLa cells. However, when FST and ANG were expressed together, they colocalized in a punctate distribution within nuclei. Mutation analysis showed that domains 2 and 3 of FST were required for ANG binding.
Weremowicz et al. (1989, 1990) assigned the human angiogenin gene to chromosome 14q11 by study of somatic cell hybrids and in situ hybridization. By study of cells containing a translocation t(11;14), they showed that the angiogenin gene is proximal to the translocation breakpoint, which is within the T-cell receptor alpha (see 186880)/delta (see 186810) locus. Steinhelper and Field (1992) mapped the Ang gene to mouse chromosome 14 by use of a PCR-RFLP mapping technique in connection with recombinant inbred strains.
Hayward et al. (1999) and Greenway et al. (2004) identified 14q11.2 as a candidate region for amyotrophic lateral sclerosis (ALS9; 611895) in Irish and Scottish populations and reported an association of a synonymous SNP in the ANG gene (rs11701) in the Irish population with ALS. Greenway et al. (2006) genotyped the rs11701 in 1,629 individuals with ALS and 1,264 controls from 5 independent populations and confirmed the association in Irish and Scottish populations with ALS, although no association was observed in populations from the U.S., England, or Sweden. Sequencing of the coding sequence of ANG and 40 bp of flanking region in the same 1,629 individuals with ALS and in 1,264 controls identified 7 heterozygous missense mutations (105850.0001-105850.0007) in 15 individuals, of whom 4 had familial and 11 'sporadic' ALS. Although mutations were present in individuals from all 5 populations, 12 of 15 affected individuals were of Scottish or Irish descent. All patients enrolled in the study had typical ALS, although a higher than expected proportion (60%) of individuals with ANG mutations had bulbar-onset disease. Common haplotypes were observed across the ANG locus and flanking region in Irish and Scottish individuals with K17I (105850.0002) and K40I (105850.0006) mutations, indicative of a founder effect. Greenway et al. (2006) also found a unique shared haplotype for the K17E mutation (105850.0003) in individuals of Swedish and northern Irish ethnicity.
Lambrechts et al. (2003) found ALS at-risk haplotypes in the VEGF promoter and leader sequence that result in reduced VEGF transcription in Swedish and English populations with ALS. Although VEGF is a putative modifier of ALS, mutations in that gene had not been found in individuals with ALS. By contrast, the study of Greenway et al. (2006) identified ANG mutations as a clear susceptibility factor for the development of ALS, particularly in individuals of Irish or Scottish descent. The findings provided further evidence that variations in hypoxia-inducible genes have an important role in ALS.
In 4 unrelated North American patients with ALS, Wu et al. (2007) identified 4 different heterozygous mutations in the ANG gene (see, e.g., 105850.0008-105850.0009), including the previously reported K17I mutation. Functional expression studies showed loss of angiogenic function of all mutant proteins.
Using yeast tRNA as substrate in a ribonucleolytic activity assay, Crabtree et al. (2007) demonstrated that 6 mutant ANG proteins (105850.0001-105850.0003; 105850.0005-105850.0007) showed substantially decreased activity, ranging from less than 1% (K40I) to 19% (K17E) of controls. The R31K (105850.0004) mutation did not show such a decrease in activity. Some of the mutant enzymes showed decreased thermal stability, and 3 variants tested showed a decrease in cell proliferative and angiogenic activities.
Gellera et al. (2008) identified 7 different ANG mutations (see, e.g., 105850.0010) in 9 (1.2%) of 737 Italian patients with ALS. The mutational frequency was higher among patients with familial disease (2.3%) compared to those with sporadic disease (1.0%). Gellera et al. (2008) found no association between ALS and rs11701 in their cohort, which included 515 controls.
Paubel et al. (2008) identified 2 different mutations (see, e.g., 105850.0007) in 3 of 855 French patients with sporadic ALS. They did not observe an association between rs11701 and the disorder in their cohort.
Subramanian et al. (2008) found that wildtype and mutant ANG, including Q12L (105850.0001), C39W (105850.0005), and K40I (105850.0006) showed substantial loss of ribonucleolytic activity compared to wildtype ANG. All 3 variants were taken up and internalized in the nuclei of pluripotent P19 embryonal carcinoma murine cells, a model of neuroectodermal differentiation. P19 cells differentiated to form neurons, but the ability of the neurites to extend and make contacts with neighboring neurites was compromised when treated with mutant ANG. The mutant ANG variants also had a cytotoxic effect on motor neurons, leading to their degeneration. Wildtype ANG was able to protect neurons from hypoxia-induced cell death, but the mutant variants lacked this neuroprotective activity. The findings showed that ANG plays an important role in neurite extension/pathfinding and survival, providing a causal link between mutations in ANG and ALS.
In a Scottish patient and an Irish/Scottish patient with amyotrophic lateral sclerosis (ALS9; 611895), Greenway et al. (2006) identified a heterozygous 107A-T transversion in the ANG gene, resulting in a gln12-to-leu (Q12L) substitution. There were no other affected members of the family.
In an Irish and an Irish/Scottish patient with amyotrophic lateral sclerosis (ALS9; 611895), Greenway et al. (2006) identified a heterozygous 122A-T transversion in the ANG gene, resulting in a lys17-to-ile (K17I) substitution. Both patients had onset at 53 years with involvement of the limbs. A common haplotype was observed across the ANG locus and flanking region in these individuals, indicative of a founder effect. The K17I mutation was also found in an apparently healthy 65-year-old male of European descent.
Wu et al. (2007) identified heterozygosity for the K17I mutation in a North American patient with ALS. In vitro functional expression studies showed that the mutant protein had less than 5% residual ribonucleolytic activity and complete loss of angiogenic function.
Van Es et al. (2009) reported a 4-generation family in which ALS segregated with the K17I mutation. Affected individuals had classic signs of the disorder, but 1 patient presented with parkinsonism and later developed signs of frontotemporal dementia. One obligate carrier did not develop the disease by age 75, indicating incomplete penetrance.
Millecamps et al. (2010) identified the K17I mutation in 2 (0.6%) of 162 French probands with familial ALS. Both showed dominant inheritance. However, 1 of the K17I carriers was also found to carry a heterozygous mutation in the FUS gene (R521C; 137070.0004), which causes ALS6 (608030).
In an individual of Swedish ethnicity and 1 of northern Irish ethnicity with amyotrophic lateral sclerosis (ALS9; 611895), Greenway et al. (2006) identified a heterozygous 121A-G transition in the ANG gene, resulting in a lys17-to-glu (K17E) substitution. The individuals shared a unique haplotype for the K17E mutation.
In an individual of Irish/English descent with a sporadic case of amyotrophic lateral sclerosis (ALS9; 611895), Greenway et al. (2006) identified a heterozygous 164G-A transition in the ANG gene, resulting in an arg31-to-lys (R31K) substitution.
Greenway et al. (2006) identified heterozygosity for a 189C-G transversion in the ANG gene, resulting in a cys39-to-trp (C39W) substitution, in 2 familial cases of amyotrophic lateral sclerosis (ALS9; 611895) with European ethnicity. In each case 3 members of the family were affected.
In 3 individuals with amyotrophic lateral sclerosis (ALS9; 611895), 2 Irish and 1 Scottish, Greenway et al. (2006) identified a heterozygous 191A-T transversion in the ANG gene, resulting in a lys40-to-ile (K40I) substitution.
In 3 Scottish individuals with amyotrophic lateral sclerosis (ALS9; 611895), Greenway et al. (2006) identified a heterozygous 208A-G transition in the ANG gene, resulting in an ile46-to-val (I46V) substitution. Two of the cases were familial.
Gellera et al. (2008) identified the I46V mutation in 6 Italian ALS patients and 4 controls (0.8% in both groups), suggesting that it is a rare polymorphism in the Italian population.
Paubel et al. (2008) identified the I46V mutation in 2 of 855 French patients with sporadic ALS. The mutation was found in 0.2% of healthy controls.
In a North American patient with amyotrophic lateral sclerosis (ALS9; 611895), Wu et al. (2007) identified a heterozygous G-to-A transition in the ANG gene, resulting in a ser28-to-asn (S28N) substitution adjacent to the nuclear localization sequence of the protein. In vitro functional expression studies showed that the mutant protein had 9% residual ribonucleolytic activity with complete loss of angiogenic function. The mutant protein was unable to translocate to the nucleus.
In a North American patient with amyotrophic lateral sclerosis (ALS9; 611895), Wu et al. (2007) identified a heterozygous C-to-T transition in the ANG gene, resulting in a pro112-to-leu (P112L) substitution. In vitro functional expression studies showed that the mutant protein had 14% residual ribonucleolytic activity with complete loss of angiogenic function. The mutant protein was unable to translocate to the nucleus.
In 2 Italian sibs and their mother with amyotrophic lateral sclerosis (ALS9; 611895), Gellera et al. (2008) identified a heterozygous 409G-A transition in the ANG gene, resulting in a val113-to-ile (V113I) substitution. The mutation was also identified in an unrelated patient with sporadic ALS who had a predominantly upper motor neuron phenotype. The mutation was not identified in 515 control individuals.
Brown, W. E., Nobile, V., Subramanian, V., Shapiro, R. The mouse angiogenin gene family: structures of an angiogenin-related protein gene and two pseudogenes. Genomics 29: 200-206, 1995. [PubMed: 8530072] [Full Text: https://doi.org/10.1006/geno.1995.1232]
Crabtree, B., Thiyagarajan, N., Prior, S. H., Wilson, P., Iyer, S., Ferns, T., Shapiro, R., Brew, K., Subramanian, V., Acharya, K. R. Characterization of human angiogenin variants implicated in amyotrophic lateral sclerosis. Biochemistry 46: 11810-11818, 2007. [PubMed: 17900154] [Full Text: https://doi.org/10.1021/bi701333h]
Gao, X., Hu, H., Zhu, J., Xu, Z. Identification and characterization of follistatin as a novel angiogenin-binding protein. FEBS Lett. 581: 5505-5510, 2007. [PubMed: 17991437] [Full Text: https://doi.org/10.1016/j.febslet.2007.10.059]
Gellera, C., Colombrita, C., Ticozzi, N., Castellotti, B., Bragato, C., Ratti, A., Taroni, F., Silani, V. Identification of new ANG gene mutations in a large cohort of Italian patients with amyotrophic lateral sclerosis. Neurogenetics 9: 33-40, 2008. [PubMed: 18087731] [Full Text: https://doi.org/10.1007/s10048-007-0111-3]
Greenway, M. J., Alexander, M. D., Ennis, S., Traynor, B. J., Corr, B., Frost, E., Green, A., Hardiman, O. A novel candidate region for ALS on chromosome 14q11.2. Neurology 63: 1936-1938, 2004. [PubMed: 15557516] [Full Text: https://doi.org/10.1212/01.wnl.0000144344.39103.f6]
Greenway, M. J., Andersen, P. M., Russ, C., Ennis, S., Cashman, S., Donaghy, C., Patterson, V., Swingler, R., Kieran, D., Prehn, J., Morrison, K. E., Green, A., Acharya, K. R., Brown, R. H., Jr., Hardiman, O. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nature Genet. 38: 411-413, 2006. [PubMed: 16501576] [Full Text: https://doi.org/10.1038/ng1742]
Hayward, C., Colville, S., Swingler, R. J., Brock, D. J. H. Molecular genetic analysis of the APEX nuclease gene in amyotrophic lateral sclerosis. Neurology 52: 1899-1901, 1999. [PubMed: 10371543] [Full Text: https://doi.org/10.1212/wnl.52.9.1899]
Hooper, L. V., Stappenbeck, T. S., Hong, C. V., Gordon, J. I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nature Immun. 4: 269-273, 2003. [PubMed: 12548285] [Full Text: https://doi.org/10.1038/ni888]
Kurachi, K., Davie, E. W., Strydom, D. J., Riordan, J. F., Vallee, B. L. Sequence of the cDNA and gene for angiogenin, a human angiogenesis factor. Biochemistry 24: 5494-5499, 1985. [PubMed: 2866795] [Full Text: https://doi.org/10.1021/bi00341a032]
Lambrechts, D., Storkebaum, E., Morimoto, M., Del-Favero, J., Desmet, F., Marklund, S. L., Wyns, S., Thijs, V., Andersson, J., van Marion, I., Al-Chalabi, A., Bornes, S., and 22 others. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genet. 34: 383-394, 2003. [PubMed: 12847526] [Full Text: https://doi.org/10.1038/ng1211]
Millecamps, S., Salachas, F., Cazeneuve, C., Gordon, P., Bricka, B., Camuzat, A., Guillot-Noel, L., Russaouen, O., Bruneteau, G., Pradat, P.-F., Le Forestier, N., Vandenberghe, N., and 14 others. SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations. J. Med. Genet. 47: 554-560, 2010. [PubMed: 20577002] [Full Text: https://doi.org/10.1136/jmg.2010.077180]
Paubel, A., Violette, J., Amy, M., Praline, J., Meininger, V., Camu, W., Corcia, P., Andres, C. R., Vourc'h, P. Mutations of the ANG gene in French patients with sporadic amyotrophic lateral sclerosis. Arch. Neurol. 65: 1333-1336, 2008. [PubMed: 18852347] [Full Text: https://doi.org/10.1001/archneur.65.10.1333]
Rybak, S. M., Fett, J. W., Yao, Q.-Z., Vallee, B. L. Angiogenin mRNA in human tumor and normal cells. Biochem. Biophys. Res. Commun. 146: 1240-1248, 1987. [PubMed: 3619929] [Full Text: https://doi.org/10.1016/0006-291x(87)90781-9]
Steinhelper, M. E., Field, L. J. Assignment of the angiogenin gene to mouse chromosome 14 using a rapid PCR-RFLP mapping technique. Genomics 12: 177-179, 1992. [PubMed: 1346389] [Full Text: https://doi.org/10.1016/0888-7543(92)90427-t]
Strydom, D. J., Fett, J. W., Lobb, R. R., Alderman, E. M., Bethune, J. L., Riordan, J. F., Vallee, B. L. Amino acid sequence of human tumor derived angiogenin. Biochemistry 24: 5486-5495, 1985. [PubMed: 2866794] [Full Text: https://doi.org/10.1021/bi00341a031]
Subramanian, V., Crabtree, B., Acharya, K. R. Human angiogenin is a neuroprotective factor and amyotrophic lateral sclerosis associated angiogenin variants affect neurite extension/pathfinding and survival of motor neurons. Hum. Molec. Genet. 17: 130-149, 2008. [PubMed: 17916583] [Full Text: https://doi.org/10.1093/hmg/ddm290]
Van Es, M. A., Diekstra, F. P., Veldink, J. H., Baas, F., Bourque, P. R., Schelhaas, H. J., Strengman, E., Hennekam, E. A. M., Lindhout, D., Ophoff, R. A., van den Berg, L. H. A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation. Neurology 72: 287-288, 2009. Note: Erratum: Neurology 72: 774 only, 2009. [PubMed: 19153377] [Full Text: https://doi.org/10.1212/01.wnl.0000339487.84908.00]
Weremowicz, S., Fox, E. A., Morton, C. C., Vallee, B. L. Localization of the human angiogenin gene to chromosome band 14q11, proximal to the T cell receptor alpha/delta locus. Am. J. Hum. Genet. 47: 973-981, 1990. [PubMed: 1978563]
Weremowicz, S., Fox, E. A., Morton, C. C. Assignment of human angiogenin gene to chromosome 14q11-q13. (Abstract) Cytogenet. Cell Genet. 51: 1107 only, 1989.
Wu, D., Yu, W., Kishikawa, H., Folkerth, R. D., Iafrate, A. J., Shen, Y., Xin, W., Sims, K., Hu, G. Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann. Neurol. 62: 609-617, 2007. [PubMed: 17886298] [Full Text: https://doi.org/10.1002/ana.21221]