Professor Geoff Woods

Understanding Mendelian disorders of neurodevelopment

General audience summary:
Mendelian disorders are inherited in families in a particular pattern that reflects the inheritance of a single mutated gene on one or both copies of the chromosome. There are more than 5000 such disorders in humans, and detailed understanding of the underlying gene changes is needed. By determining the DNA codes of family groups with new disorders, it can be possible to find the gene mutation that is responsible for that disease. We are currently focusing on the inherited disorders that result in the inability to feel pain or conversely excess pain. Our work has found the genes that are responsible for some of these disorders, and our hope is that these findings may contribute to the development of new painkillers.

Strategic CIMR themes: Rare Genetic Diseases, Neurological Diseases

Funding: Wellcome Trust, BBSRC, Cambridge NIHR Biomedical Research Centre, Addenbrooke's Charitable Trust, Open Targets

Research Group members: Ichrak Drissi, Kathleen Ng, Samiha Shaikh, Yunisa Pamela, Shalini Roy Choudhury

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Research

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.

Publications

Key publications:

Nahorski MS, Maddirevula S, Ishimura R, Alsahli S, Brady AF, Begemann A, Mizushima T, Guzmán-Vega FJ, Obata M, Ichimura Y, Alsaif HS, Anazi S, Ibrahim N, Abdulwahab F, Hashem M, Monies D, Abouelhoda M, Meyer BF, Alfadhel M, Eyaid W, Zweier M, Steindl K, Rauch A, Arold ST, Woods CG, Komatsu M & Alkuraya FS. Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development. Brain 141(7):1934-1945 (2018).

Schon K, Parker A, Woods CG. Congenital Insensitivity to Pain Overview.
In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Chavali PL, Stojic L, Meredith LW, Joseph N, Nahorski MS, Sanford TJ, Sweeney TR, Krishna BA, Hosmillo M, Firth AE, Bayliss R, Marcelis CL, Lindsay S, Goodfellow I, Woods CG, Gergely F. Neurodevelopmental protein Musashi-1 interacts with the Zika genome and promotes viral replication. Science 357(6346):83-88 (2017).

Shaikh SS, Chen YC, Halsall SA, Nahorski MS, Omoto K, Young GT, Phelan A, Woods CG. A Comprehensive Functional Analysis of NTRK1 Missense Mutations Causing Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV).
Hum Mutat. 38(1):55-63 (2017).

Nahorski MS, Asai M, Wakeling E, Parker A, Asai N, Canham N, Holder SE, Chen YC, Dyer J, Brady AF, Takahashi M, Woods CG. CCDC88A mutations cause PEHO-like syndrome in humans and mouse. Brain 139(Pt 4):1036-44 (2016).

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, Woods CG. A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development. Brain 138(Pt 8):2147-60 (2015).

Nahorski MS, Chen YC, Woods CG. New Mendelian Disorders of Painlessness.
Trends Neurosci. 38(11):712-724 (2015).

Waxman SG, Merkies ISJ, Gerrits MM, Dib-Hajj SD, Lauria G, Cox JJ, Wood JN, Woods CG, Drenth JPH, Faber CG. Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use. Lancet Neurol. 13(11):1152-1160. doi:10.1016/S1474-4422(14)70150-4 (2014)

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).

Understanding Mendelian disorders of neurodevelopment

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Research

Publications

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Research at Cambridge