Generally, sampling cells from more extreme tails by decreasing the fluorescence cutoff for selection increased power; however, mutations causing very large increase or decrease in the standard deviation of the fluorescence phenotype were found to require a particular range of cutoff percentages to maximize power.
Slc11a2 proteins play a central role in iron homeostasis, and a loss-of-function mutation (G185R) causes very severe microcytic anemia in the mk mouse and in the Belgrade rat (14, 15).
Therefore, V263M mutation would cause very limited influence to the folding and stability of the protein.
Nevertheless, it is clear that the same mutation can cause very different phenotypes between patients and an important variable that separates individual cases is the nuclear background.
However, it remains unclear how such 'gain-of-function' mutations might cause very similar, if not identical phenotypes as a loss-of-function, as observed with Clcn7−/− mice and several human mutations.
Mouse knockout studies show that NFIA mutation results in hydrocephalus and abnormal brain development [8], NFIB mutation causes retarded lung development [9] and NFIC mutation causes abnormal tooth development [10], with very little overlap in phenotypes.
Furthermore, elg1 Δ caused very similar effects to cac1 Δ and cac2 Δ mutations in all polymerase-defective strains.
In fact, most lethal mutations cause only very rare diseases.
Mouse models for the different mutations causing thalassemia are, therefore, very important to test in vivo the activity of new potential approaches that target specific mutations [ 19].
Replication bypass of the cross-link was less accurate than that of the parent γ-OH-PdG adduct 2 (∼3.5% of mutations), while the spectra of mutations caused by these lesions were very similar.
