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Heterozygous NTF4 mutations impairing neurotrophin-4 signaling in patients with primary open-angle glaucoma

Pasutto, Francesca, Matsumoto, Tomoya, Mardin, Christian Y., Sticht, Heinrich, Brandstätter, Johann H., Michels-Rautenstrauss, Karin, Weisschuh, Nicole, Gramer, Eugen, Ramdas, Wishal D., van Koolwijk, Leonieke M.E., Klaver, Caroline C.W., Vingerling, Johannes R., Weber, Bernhard H.F., Kruse, Friedrich E., Rautenstrauss, Bernd, Barde, Yves-Alain and Reis, André 2009. Heterozygous NTF4 mutations impairing neurotrophin-4 signaling in patients with primary open-angle glaucoma. American Journal of Human Genetics 85 (4) , pp. 447-456. 10.1016/j.ajhg.2009.08.016

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Glaucoma, a main cause of blindness in the developed world, is characterized by progressive degeneration of retinal ganglion cells (RGCs), resulting in irreversible loss of vision. Although members of the neurotrophin gene family in various species are known to support the survival of numerous neuronal populations, including RGCs, it is less clear whether they are also required for survival and maintenance of adult neurons in humans. Here, we report seven different heterozygous mutations in the Neurotrophin-4 (NTF4) gene accounting for about 1.7% of primary open-angle glaucoma patients of European origin. Molecular modeling predicted a decreased affinity of neurotrophin 4 protein (NT-4) mutants with its specific tyrosine kinase receptor B (TrkB). Expression of recombinant NT-4 carrying the most frequent mutation was demonstrated to lead to decreased activation of TrkB. These findings suggest a pathway in the pathophysiology of glaucoma through loss of neurotrophic function and may eventually open the possibility of using ligands activating TrkB to prevent the progression of the disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > RE Ophthalmology
Publisher: American Society of Human Genetics
ISSN: 0002-9297
Last Modified: 04 Jun 2017 05:21

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