Understanding Mendelian disorders of neurodevelopment
Our research derives from patients with Mendelian disorders of neurodevelopment. The results are of use to the families and their clinicians, and define essential genes and processes in human neurodevelopment.
Our studies are primarily translational:
- We ascertain, study and classify people/families with genetic diseases through specialist clinics and extensive collaboration.
- We discover the causative genes for the phenotypes associated with these diseases by characterizing potential pathogenic mutations.
- We perform whatever further studies are needed to prove mutations are pathogenic, define the function of the gene in normal development, and determine how mutation leads to disease phenotypes.
- Finally, we offer clinical support and molecular genetic diagnosis through the NHS East Anglian Genetics Service.
Our current main focus is Mendelian disorders of painlessness and of excess pain, ascertained from Paediatric and Adult Neurology, Rheumatology, Pain clinics and my clinical work. We are part of a CamPain network of Cambridge physicians and scientists seeking to understand painful disorders and produce better treatments. Together we are developing methods to assess nociceptor spinal cord and central nervous system responses in pain disorders, with our team's contribution being to identify and investigate potential underlying driver genetic changes. We also study painlessness which can be classified as: failures of the pain-sensing nervous system to develop; inability of pain-sensing neurons to respond to nociceptive stimuli; or neuropathies that uniquely or particularly affect peripheral nociceptors. We work on new disorders in each category. For example, in collaboration with Professor Vallier in the Stem Cell Centre and MedImmune, we are investigating the 'créer' events that allow a mitotically active neural crest progenitor to change into a post-mitotic nociceptor. The genes regulating these developmental steps, such as TRKA and NGF, will have other essential post-natal roles in pain — and hence are candidates to generate novel analgesics.
Chen YC et al. Transcriptional regulator PRDM12 is essential for human pain perception. Nature Genet. 47, 803–808 (2015).
Nahorski MS, Al-Gazali L, Hertecant J, Owen DJ, Borner GH, Chen YC, Benn CL, Carvalho OP, Shaikh SS, Phelan A, Robinson MS, Royle SJ & Geoffrey Woods C. A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development. Brain 138, 2147–2160 (2015).
Woods CG* & Bennett D*. Painful and painless channelopathies – invited review. Lancet Neurol. 13, 587–599 (2014). *corresponding authors.
Woods CG & Parker A. Investigating microcephaly. Arch Dis Child. 98, 707–713 (2013).
Weiss, J., Pyrski, M., Jacobi, E., Bufe, B., Willnecker, V., Schick, B., Zizzari, P., Gossage, S.J., Greer, C.A., Leinders-Zufall, T., Woods, C.G., Wood, J.N. and Zufall, F. Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature 472, 186–190 (2011).
Sir, J.H., Barr, A.R., Nicholas, A.K., Carvalho, O.P., Khurshid, M., Sossick, A., Reichelt, S., D'Santos, C., Woods, C.G.* and Gergely, F.* A primary microcephaly protein complex forms a ring around parental centrioles. Nature Genet. 43, 1147–1153 (2011). * corresponding authors.
Cox, J.J., Willatt, L., Homfray, T. and Woods, C.G. A SOX9 duplication and familial 46,XX developmental testicular disorder. N. Engl. J. Med. 364, 91–93 (2011).
Cox, J. J., Sheynin, J., Shorer, Z., Reimann, F., Nicholas, A. K., Zubovic, L., Baralle, M., Wraige, E., Manor, E., Levy, J., Woods, C. G. and Parvari, R. Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations. Hum. Mutat. 31, E1670–1686 (2010).
Reimann, F., Cox, J. J., Belfer, I., Diatchenko, L., Zaykin, D. V., McHale, D. P., Drenth, J. P., Dai, F., Wheeler, J., Sanders, F., Wood, L., Wu, T. X., Karppinen, J., Nikolajsen, L., Männikkö, M., Max, M. B., Kiselycznyk. C., Poddar, M., Te Morsche, R. H., Smith, S., Gibson, D., Kelempisioti, A., Maixner, W., Gribble, F. M. and Woods. C. G. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc. Natl Acad. Sci. USA 107, 5148–5153 (2010).
Jacoby, M., Cox, J. J., Gayral, S., Hampshire, D. J., Ayub, M., Blockmans, M., Pernot, E., Kisseleva, M. V., Compère, P., Schiffmann, S. N., Gergely, F., Riley, J. H., Pérez-Morga, D., Schurmans, S. and Woods, C. G. INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nature Genet. 41, 1027–1031 (2009).
Cox, J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. and Woods, C. G. SCN9A channelopathy cause a congenital inability to experience pain. Nature 444, 894–898 (2006).