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

Abstract

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.

• Authors: Francesca Pasutto, Tomoya Matsumoto, Christian Y Mardin, Heinrich Sticht, Johann H Brandstätter, Karin Michels-Rautenstrauss, Nicole Weisschuh, Eugen Gramer, Wishal D Ramdas, Leonieke M E van Koolwijk, Caroline C W Klaver, Johannes R Vingerling, Bernhard H F Weber, Friedrich E Kruse, Bernd Rautenstrauss, Yves-Alain Barde, André Reis
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 85 Issue 4 Pg. 447-56 (Oct 2009) ISSN: 1537-6605 [Electronic] United States
• PMID: 19765683 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Growth Factors
• Receptor, trkB
• neurotrophin 4

Topics

• Adult
• Aged
• Aged, 80 and over
• Disease Progression
• Female
• Glaucoma, Open-Angle (genetics, pathology)
• Heterozygote
• Humans
• Male
• Middle Aged
• Mutation
• Nerve Growth Factors (genetics)
• Neurons (metabolism)
• Receptor, trkB (genetics)
• Signal Transduction