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 ... 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.
Greenway et al. (2004) reported an association between ALS and a synonymous SNP in the ANG gene (dbSNP rs11701) in an Irish population. Among in 1,629 individuals with ALS and 1,264 controls from 5 independent populations, Greenway et ... Greenway et al. (2004) reported an association between ALS and a synonymous SNP in the ANG gene (dbSNP 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 dbSNP 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 dbSNP 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 dbSNP 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).