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In our simulations, however, mutations affect phenotype in a cumulative way such that each mutation causes only a partial loss of protein function.
The mild phenotype presented by this patient and his long survival, together with his response to Cu-His treatment, suggest that the p.T1048I mutation causes only a partial loss of ATP7A function, which probably does not completely block copper transport across the blood brain barrier and therefore results in moderate neurological impairment.
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Unlike the NL3 R451C mutation, the R704C mutation caused only a roughly 35% reduction in NL3 expression [ 39].
Apparently, the rpl24b mutation caused only a minor deficiency in ribosome loading for the uORF-containing mRNAs.
Interestingly, the F180L mutation caused only about a two-fold decrease in the deacetylation activity of the enzyme.
Interestingly, the F180L mutation caused only around 2-fold decrease in the enzyme's deacetylation activity (see Figure 4 figure supplement 6).
The lack of PCD activation in the Sec24A mutant may be linked to the fact that the missense mutation caused only a partial loss of Sec24A function, affecting the anterograde trafficking of only a subset of cargos [ 39].
However, even if the mutation caused only partial ICR1 demethylation to take place in the female germline (grandmother and daughters), one would still expect less ICR1 methylation in third generation (the children with BWS), not more.
Current thinking is that major gene mutations cause only a small proportion of all cases and that in most cases, non-genetic factors play a part, probably in interaction with susceptibility genes.
In fact, most lethal mutations cause only very rare diseases.
If individual mutations cause only minor changes in phenotypes, gene flow and recombination might prevent adaptation to local environments [ 77].
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