Article

Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis

Department of Pathology, Brigham and Women's Hospital, Boston, MA 02114, USA.
Annals of Neurology (Impact Factor: 11.91). 12/2007; 62(6):609-17. DOI: 10.1002/ana.21221
Source: PubMed

ABSTRACT Heterozygous missense mutations in the coding region of angiogenin (ANG), an angiogenic ribonuclease, have been reported in amyotrophic lateral sclerosis (ALS) patients. However, the role of ANG in motor neuron physiology and the functional consequences of these mutations are unknown. We searched for new mutations and sought to define the functional consequences of these mutations.
We sequenced the coding region of ANG in an independent cohort of North American ALS patients. Identified ANG mutations were then characterized using functional assays of angiogenesis, ribonucleolysis, and nuclear translocation. We also examined expression of ANG in normal human fetal and adult spinal cords.
We identified four mutations in the coding region of ANG from 298 ALS patients. Three of these mutations are present in the mature protein. Among the four mutations, P(-4)S, S28N, and P112L are novel, and K17I has been reported previously. Functional assays show that these ANG mutations result in complete loss of function. The mutant ANG proteins are unable to induce angiogenesis because of a deficiency in ribonuclease activity, nuclear translocation, or both. As a correlate, we demonstrate strong ANG expression in both endothelial cells and motor neurons of normal human spinal cords from the developing fetus and adult.
We provide the first evidence that ANG mutations, identified in ALS patients, are associated with functional loss of ANG activity. Moreover, strong ANG expression, in normal human fetal and adult spinal cord neurons and endothelial cells, confirms the plausibility of ANG dysfunction being relevant to the pathogenesis of ALS.

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    • "On the other hand, low expression levels, mislocalization and/or cellular inclusions have been shown in neurodegenerative cells; all of which may negatively affect the normal amount of certain RBPs in a specific subcellular location. Furthermore, loss-offunction has been demonstrated for ANG mutants involved in neurodegeneration (Wu et al. 2007). "
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    • "So far , no human disease has been associated with mutations in Dnmt2 , but similar to NSun2 , also mutations in angiogenin are linked to neurological disorders ( van Es et al , 2011 ) . Neuro - develop - mental and intellectual disabilities are further commonly associated with oxidative stress ( Wu et al , 2007 ; De Felice et al , 2012 ; Lintas et al , 2012 ) . "
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    • "Our simulation results correlate with reported experimental data without exception [5] [6] [31]. To make this method widely accessible to researchers and clinicians, we created a web server based tool, ANGDelMut, freely available at http://bioschool.iitd.ernet.in/research "
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