Pain and swelling, suffering and love: the NGF story

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• Dr. Geoff Woods, Department of Genetics, Cambridge
• Tuesday 29 September 2009, 10:00-10:30
• West Road Concert Hall.

If you have a question about this talk, please contact Hannah Critchlow.

This talk is part of the Cambridge Clinical Neuroscience and Mental Health Symposium, 29th – 30th September 2009 at West Road Concert Hall. This event is free to attend for cambridge neuroscientists although registration is required. To register, and for further information, please visit: http://www.neuroscience.cam.ac.uk/cnmhs/

Abstract: We study rare individuals who feel no pain. My presentation describes a homozygous mis-sense mutation in Nerve Growth Factor gene in such a family. The phenotype is different from the only other report in the literature. The phenotype (unsurprisingly) is identical to that of TRKA mutations; TRKA is the receptor for NGF on pain sensing neurons. Our functional studies have assessed the ability of both our and the previous mutation to induce neuron differentiation using a PC12 model. This was used as NGF is a known inductor of neuronal differentiation in this cell line. Our mutation was a null. We have also assessed the trafficking and excretion of our NGF mutation. The mutation affects the N-terminal domain of the secreted NGF -Beta protein. However, we have found that it is NGF cleavage to form the NGF -Beta that is deficient. Finally we have observed an immune phenotype in our patients – which may have been expected given the role of NGF -Beta in inflammation. As NGF -Beta also causes hyper-excitability to pain sensing neurons it explains why infective lesions swell and are painful, and the rational for developing NGF -Beta blockers are analgesics. Our work suggests that such drugs should be used with caution as they may cause immune-deficiency.

References:

Nilsen KB, et al. Two novel SCN9A mutations causing insensitivity to pain. Pain. 2009 May;143(1-2):155-8.

Cox JJ, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 14;444(7121):894-8.

Biosketch: I am a Paediatrician who changed to a Clinical Geneticist as they were more involved in the cause of mental retardation than in its treatment. I still see myself as a Paediatrician however. Along the way I have worked in Vancouver, Melbourne and Oxford in my training phase, and Leeds as a consultant where I began to be interested in clinically led research. I moved to Cambridge in 2005 and have a research team dedicated to finding genes that cause Mendelian diseases – that is where a gene change, alone and always, causes a significant human phenotype change. Clinically my main interest is diseases that stop the human brain growing to its potential enormous size; viewed from an evolutionary point of view!. The common mechanism appears to be dysfunction of the centrosome somewhat surprisingly. We also have a significant interest in finding genes that control pain sensing in humans and in understanding how disease mutations then cause human disease phenotypes – which is never as straight forward as it should be!

This talk is part of the Clinical Neuroscience and Mental Health Symposium series.

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