We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration.
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We are indebted to the patients, their families and referring neurologists for their participation in this project. We thank the following for their assistance with this study: M. Rogers, B. O'Hici, M. Russell, P. Connolly and D. Barton of the National Centre for Medical Genetics, Dublin, Ireland; E. Frost of the Irish Motor Neurone Disease Association; B. Corr, O. O'Toole, M. Alexander, B. Traynor and C. Lynch of Beaumont Hospital, Dublin, Ireland; D. McKenna-Yasek, W. Broom, S. Benn and P. Sapp of the Day Neuromuscular Research Laboratory, Boston; I. McLean of the University of Dundee; E. Goodall, H. Pall and K. Poulton of the University of Birmingham and S. Iyer of the University of Bath for the molecular modeling study on ANG mutants and Figure 1b. This work was supported in part by grants from the Health Research Board of Ireland (to M.G. and O.H.) and the Northern Ireland Research Office (V.P., C.D. and O.H.); by the Swedish Medical Society, the Björklund Foundation for ALS Research and the Hållstens Research Foundation (to P.A.); by the Wellcome Trust (UK) program grant 067288 (to K.R.A.); by the Scottish Motor Neurone Disease Association and the Scottish Home and Health Department (to R.S.); by the Motor Neurone Disease Association UK (to K.E.M.) and by the US National Institute of Neurological Disorders and Stroke, Project ALS, the ALS Association, the Al-Athel ALS Foundation and the Angel Fund (to R.H.B. and C.R.).
M.J.G. and O.H. are listed as inventors on a patent (UK patent number 0425625.1, 'Treatment of disease (use of angiogenin in neurodegenerative and axonal disease)') submitted to the UK Patent Office by the Royal College of Surgeons in Ireland.
Angiogenin is expressed in mouse spinal cord motor neurons. (PDF 136 kb)
Expression of angiogenin in primary motoneuron cultures prepared from mouse. (PDF 3008 kb)
Clinical details of study populations. (PDF 24 kb)
Frequency of ANG rs11701 SNP genotypes. (PDF 34 kb)
Marker data for individuals with K17I and K40I mutations. (PDF 18 kb)
Amino acid residues involved in van der Waals contacts and hydrogen bonding interactions in the native crystal structure of ANG and mutated models. (PDF 16 kb)
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Greenway, M., Andersen, P., Russ, C. et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet 38, 411–413 (2006). https://doi.org/10.1038/ng1742