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 Neurology and Clinical Genetics. These conditions can be classified arbitrarily as: failures of the pain-sensing nervous system to develop; inability of pain-sensing neurons to respond to nociceptive stimuli; and neuropathies that uniquely or particularly affect peripheral nociceptors. We work on new disorders in each category. In collaboration with Neusentis, we are investigating the 'créer' events that allow a mitotically active neural crest progenitor to change into a post-mitotic nociceptor. It is possible that 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.
We are also trying to determine the genetic factors that affect pain threshold, risk of neuropathic/chronic pain, and response to analgesics. We are building up cohorts with high pain threshold and various types of neuropathic pain. Through integrated phenotype and genotype data, we are seeking significant genetic changes, and to find those which may have clinical use.
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).