Mutations in gamma adducin are associated with inherited cerebral palsy
Article first published online: 21 JAN 2014
© 2013 American Neurological Association
Annals of Neurology
Volume 74, Issue 6, pages 805–814, December 2013
How to Cite
Kruer, M. C., Jepperson, T., Dutta, S., Steiner, R. D., Cottenie, E., Sanford, L., Merkens, M., Russman, B. S., Blasco, P. A., Fan, G., Pollock, J., Green, S., Woltjer, R. L., Mooney, C., Kretzschmar, D., Paisán-Ruiz, C. and Houlden, H. (2013), Mutations in gamma adducin are associated with inherited cerebral palsy. Ann Neurol., 74: 805–814. doi: 10.1002/ana.23971
- Issue published online: 21 JAN 2014
- Article first published online: 21 JAN 2014
- Accepted manuscript online: 9 JUL 2013 05:21AM EST
- Manuscript Accepted: 7 JUN 2013
- Manuscript Revised: 27 MAY 2013
- Manuscript Received: 10 APR 2013
- American Academy of Neurology (Clinical Research Training Fellowship awarded to M.C.K.)
- American Philosophical Society
- Child Neurology Foundation
- NIH. Grant Number: NINDS K08NS083739
- American Academy of Cerebral Palsy and Developmental Medicine
- Medical Research Council. Grant Numbers: MRC fellowships G108=638, G0802760, Wellcome Trust=MRC Joint Call in Neurodegeneration award WT089698
- National Institute of Neurological Disorders and Stroke. Grant Number: R01NS079388
Cerebral palsy is estimated to affect nearly 1 in 500 children, and although prenatal and perinatal contributors have been well characterized, at least 20% of cases are believed to be inherited. Previous studies have identified mutations in the actin-capping protein KANK1 and the adaptor protein-4 complex in forms of inherited cerebral palsy, suggesting a role for components of the dynamic cytoskeleton in the genesis of the disease.
We studied a multiplex consanguineous Jordanian family by homozygosity mapping and exome sequencing, then used patient-derived fibroblasts to examine functional consequences of the mutation we identified in vitro. We subsequently studied the effects of adducin loss of function in Drosophila.
We identified a homozygous c.1100G>A (p.G367D) mutation in ADD3, encoding gamma adducin in all affected members of the index family. Follow-up experiments in patient fibroblasts found that the p.G367D mutation, which occurs within the putative oligomerization critical region, impairs the ability of gamma adducin to associate with the alpha subunit. This mutation impairs the normal actin-capping function of adducin, leading to both abnormal proliferation and migration in cultured patient fibroblasts. Loss of function studies of the Drosophila adducin ortholog hts confirmed a critical role for adducin in locomotion.
Although likely a rare cause of cerebral palsy, our findings indicate a critical role for adducins in regulating the activity of the actin cytoskeleton, suggesting that impaired adducin function may lead to neuromotor impairment and further implicating abnormalities of the dynamic cytoskeleton as a pathogenic mechanism contributing to cerebral palsy. Ann Neurol 2013;74:805–814