SNOMEDCT: 1204351003; ORPHA: 803; DO: 0060200;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q11.2 | Amyotrophic lateral sclerosis 9 | 611895 | 3 | ANG | 105850 |
A number sign (#) is used with this entry because of evidence that amyotrophic lateral sclerosis-9 (ALS9) is caused by heterozygous mutation in the angiogenin gene (ANG; 105850) on chromosome 14q11.
For a general phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Van Es et al. (2009) reported a 4-generation family with autosomal dominant ALS due to ANG mutation. Affected individuals had classic signs of the disorder, including progressive upper and lower motor neuron loss affecting the limbs, 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.
Hayward et al. (1999) and Greenway et al. (2004) identified chromosome 14q11.2 as a candidate region for ALS in Irish and Scottish populations.
Greenway et al. (2004) reported an association between ALS and a synonymous SNP in the ANG gene (rs11701) in an Irish population. Among in 1,629 individuals with ALS and 1,264 controls from 5 independent populations, Greenway et al. (2006) confirmed the association between ALS and rs11701. However, the association was observed in Irish and Scottish populations, but not in populations from the U.S., England, or Sweden. Greenway et al. (2006) identified 7 missense mutations in the ANG gene (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 (192240) promoter and leader sequence that result in reduced VEGF transcription in the 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 of 298 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.
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.
Van Es et al. (2009) identified heterozygosity for the K17I mutation in affected individuals from a 4-generation family with ALS.
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).
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]
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]
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]
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]