Overall, a concept emerges according to which the amount and severity of mutations in functionally related genes are crucial for the clinical phenotype.
An age-related exacerbation of the severity of mutation-induced metabolic/structural complications occurs for each genotype mutation.
Indeed, the biochemical severity of mutations associated with diseases that manifest the earliest is 17% higher than the latest-onset diseases (P < 0.05).
The chemical severity of amino acid changes may depend on the expected chemical severity of mutations that can arise from a single nucleotide substitution in the codon involved [ 21].
Although most cblA patients present in infancy or childhood with methylmalonic aciduria and potentially life-threatening acidotic crises (Ref. 104), they often respond to vitamin B12 therapy despite the severity of mutations (Refs 104, 124, 125).
However, when the percentage of mutant mtDNA exceeds a threshold in the range of 60% 95%, depending on the severity of the mutation, pathogenic mtDNA mutations can lead to various clinical manifestations (Russell and Turnbull, 2014).
Based on studies of KIT mutations in mice, the severity of this mutation suggests that it may be nonviable in the homozygous state.
The observed structural and biochemical abnormalities correlate with the severity of the mutation, with the COG4 mutant being the mildest.
We have applied several bioinformatic approaches to predict the severity of each mutation and to model the effects on protein structure.
