Mutation detection

Miniaturization, 128, 163, 193 Minigrid electrode, 41, 52 Mixed-salt electrodes, 159 Modified electrodes, 118, 121 Monensin, 155 Monolayers, 117, 118, 173 Multichannel electrodes, 93, 94 Multipotentiostat, 106, 198 Mutation detection, 185... 

These three NIST SRMs have a number of important quality control applications for forensic DNA profiling, medical diagnostics and mutation detection. The main applications are summarized below ... 

Ievin BC, Cheng H and Reeder DJ (1999) A human mitochondrial DNA standard reference material for quality control in forensic identification, medical diagnosis, and mutation detection. Genomics 55 135-146. 

Analysis of Genetic Variability by PCR-coupled Mutation Detection Methods... 

Cotton, R.G.H. (1997) Mutation Detection. Oxford University Press, Oxford. 

Specifically, for genetic tests the sponsor should present evidence of sensitivity in terms not only of the ability of the test to detect specific mutation (analytic sensitivity), but also of the proportion of people with clinically significant disease that are detected by the test (e.g., who have the specific mutation detected by the test clinical sensitivity). 

Figure 4.2 The spectrum of p53 mutations detected in oesophageal adenocarcinoma tumours. Data were downloaded from the lARC database and based on an analysis of 260 separate mutation profiles.

Mutation detection — Genetic mutations leading to disease states such as familial breast cancer can be detected by arrays, provided that sufficient gene probe sequence content is available in order to make a statistically significant prognosis. 

This chapter will review some of the key applications presented by protein microarrays. The use of profein microarrays sfems from works on gene expression arrays described earlier. However, rmlike ifs predecessors whose process formats (mutation detection, polymorphism screening, gene expression analysis, etc.) are essentially based upon solid-phase hybridization of nucleic acid complementary strands, the protein array may play different roles and comprise a variety of formafs. 

Lizardi, P.M., Huang, H., Zhu, Z., Bray-Ward, P, Thomas, D.C., and Ward, D.C., Mutation detection and single-molecule counting using isothermal rolling circle amplification, Nat. Genetics, 19, 225-232, 1998. 

El. Forrest, S. M., Dahl, H. H., et al, Mutation detection in phenylketonuria by using chemical cleavage of mismatch Importance of using probes from both normal and patient samples. Am. J. Hum. Genet. 49(1), 175-183 (1991). 

Fig. 4. Map of BCR-ABL kinase domain mutations associated with clinical resistance to imatinib. Abbreviations P, P-loop B, imatinib binding site C, catalytic domain A, activation loop. Amino-acid substitutions in green indicate mutations detected in 2-10% and in red in >10% of patients with mutations. (Reprinted with permission from Ref (52)).

Several studies have suggested that patients with IM resistance secondary to mutations in the P-loop have a poorer prognosis than patients with mutations in other portions of the ABLl kinase domain. A study from Australia detected mutations in 27 of 144 patients at 17 different residues. Twenty-four of these 27 patients (89%) developed acquired resistance. Thirteen of these 24 had mutations in the P-loop, and 12 of these patients died with a median survival of only 4.5 months after mutation detection. 

Cazzaniga G, Corradi B, Piazza R et al. Highly sensitive mutations detection in BCR-ABL positive leukemia prior and during imatinib treatment (Abstract 1985). Blood2004 104 548a. 

Commercial LightCycler-apoB mutation detection kit (Roche Molecular Biochemicals). 

---