David Bonthron

By autozygosity mapping, we showed that the PMS2 DNA repair gene is mutated in a recessive syndrome of brain and haematological malignancies of childhood. Numerous pseudogenes make mutation analysis of PMS2 very difficult. We have further found that gene conversion involving one of these pseudogenes generates a great deal of PMS2 polymorphic variation; such conversion events can also be a source of cryptic genetic pathology.

We also have a longstanding interest in disorders of genomic imprinting in humans. We have characterised the genetic defect in a series of families with recurrent hydatidiform mole (MIM:231090), a disorder of imprinting in the developing oocyte. This disorder can result from homozygous mutations of the NALP7 gene, but we have also shown that it is genetically heterogeneous.

With Chris Bennett and other colleagues, we have shown that primary hypertrophic osteoarthropathy is a defect of prostaglandin metabolism, which also helps to explain why finger clubbing develops in so many human disease states.

Judson H, Hayward BE, Sheridan E, Bonthron DT (2002) A global disorder of imprinting in the female germline. Nature 416: 539-43

De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT (2004) Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 74:954-64.

Carr IM, Flintoff KJ, Taylor GR, Markham AF, Bonthron DT (2006) Interactive visual analysis of SNP data for rapid autozygosity mapping in consanguineous families. Hum Mutat 27:1041-6.

Hayward BE, De Vos M, Valleley EM, Charlton RS, Taylor GR, Sheridan E, Bonthron DT (2007) Extensive gene conversion at the PMS2 DNA mismatch repair locus. Hum Mutat 28:424-30.

Uppal S, Diggle CP, Carr IM, Fishwick CWG, Ahmed M, Ibrahim GH, Helliwell PS, Latos-Bielenska A, Phillips SEV, Markham AF, Bennett CP, Bonthron DT (2008) Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nature Genet 40:789–93.