Journal article
Mutations in TNK2 in severe autosomal recessive infantile onset epilepsy.
Y Hitomi, EL Heinzen, S Donatello, HH Dahl, JA Damiano, JM McMahon, SF Berkovic, IE Scheffer, B Legros, M Rai, S Weckhuysen, A Suls, P De Jonghe, M Pandolfo, DB Goldstein, P Van Bogaert, C Depondt
Annals of Neurology | Published : 2013
DOI: 10.1002/ana.23934
Abstract
We identified a small family with autosomal recessive, infantile onset epilepsy and intellectual disability. Exome sequencing identified a homozygous missense variant in the gene TNK2, encoding a brain-expressed tyrosine kinase. Sequencing of the coding region of TNK2 in 110 patients with a similar phenotype failed to detect further homozygote or compound heterozygote mutations. Pathogenicity of the variant is supported by the results of our functional studies, which demonstrated that the variant abolishes NEDD4 binding to TNK2, preventing its degradation after epidermal growth factor stimulation. Definitive proof of pathogenicity will require confirmation in unrelated patients. Copyright © ..
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Awarded by National Institute of Neurological Disorders and Stroke
Funding Acknowledgements
This study was funded by the NIH National Institute of Neurological Diseases and Stroke (1RC2NS070342-01, 5RC2NS070344-02); Division of Intramural Research, NIH National Institute of Allergy and Infectious Diseases; Center for HIV/AIDS Vaccine Immunology under a grant from the NIH National Institute of Allergy and Infectious Diseases (UO1AIO67854); National Health and Medical Research Council of Australia (program grant 2011-2015); and Fonds Erasme, Universite Libre de Bruxelles. A.S. is a postdoctoral fellow of the Fund for Scientific Research Flanders. We thank the NIH National Heart, Lung, and Blood Institute GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010); the patients and their families for participating in this research; the Epigen Consortium for making their samples available for genotyping: Drs S. Sisodiya, N. Delanty, and G. Cavalleri; and the following individuals for the contributions of control samples: Dr J. Hoover-Fong, Dr N. L. Sobreira, Dr D. Valle, D. H. Murdock and the MURDOCK Study Community Registry and Biorepository, Dr E. J. Holtzman, Dr D. Koltai Attix, V. Dixon, Dr V. Shashi, Dr W. L. Lowe, Dr S. M. Palmer, Dr D. Marchuk, Dr Z. Farfel, Dr D. Lancet, Dr E. Pras, Dr J. Milner, Dr D. Daskalakis, Dr R. Gbadegesin, Dr M. Winn, A. Holden, Dr E. Behr, Dr R. H. Brown Jr, Dr S. Kerns, Dr H. Oster, and Dr M. Abramowicz.