Mutation, SNP and isoform analysis of fibroblast growth factor receptor 3 (FGFR3) in 150 newly diagnosed multiple myeloma patients

The t(4;14) translocation in multiple myeloma (MM) is identified in ∼15% of patient samples, dysregulating FGFR3 and MMSET. Activating FGFR3 mutations are observed in myeloma cell lines and in late stage MM but the incidence of mutation in newly diagnosed patient samples is unknown. Gene expression profiling of 150 newly diagnosed patients revealed FGFR3 over-expression in 24 (16%). RT-PCR and FISH confirmed that all of the FGFR3 positive patients carried the t(4;14) translocation. Sequencing of the entire open reading frame of FGFR3 gene identified an insertion of two amino acids in one patient and a Y241C point mutation in another. Moreover, two isoforms of FGFR3 that have not previously been described in MM were identified. Furthermore, we identified the C294T polymorphism in 17 of 22 patient samples. Therefore mutations of FGFR3 occur in less than 5% of t(4;14) positive and in less than 1% of newly diagnosed myeloma patients overall.M.Sc

Identification of multiple quantitative trait loci linked to prion disease incubation period in mice

Polymorphisms in the prion protein gene are known to affect prion disease incubation times and susceptibility in humans and mice. However, studies with inbred lines of mice show that large differences in incubation times occur even with the same amino acid sequence of the prion protein, suggesting that other genes may contribute to the observed variation. To identify these loci we analyzed 1,009 animals from an F2 intercross between two strains of mice, CAST/Ei and NZW/OlaHSd, with significantly different incubation periods when challenged with RML scrapie prions. Interval mapping identified three highly significantly linked regions on chromosomes 2, 11, and 12; composite interval mapping suggests that each of these regions includes multiple linked quantitative trait loci. Suggestive evidence for linkage was obtained on chromosomes 6 and 7. The sequence conservation between the mouse and human genome suggests that identification of mouse prion susceptibility alleles may have direct relevance to understanding human susceptibility to bovine spongiform encephalopathy (BSE) infection, as well as identifying key factors in the molecular pathways of prion pathogenesis. However, the demonstration of other major genetic effects on incubation period suggests the need for extreme caution in interpreting estimates of variant Creutzfeldt-Jakob disease epidemic size utilizing existing epidemiological models