The phenotypic variability often shown among ciliopathy patients carrying the same combinations of mutations has suggested the presence of modifier genes and/or the involvement of tri-allelic inheritance [ 28- 32].
Clinical implications Previous studies of KCNJ11 mutations have suggested that there is a good correlation between the percentage of current that remains unblocked in the presence of 3 mmol/l MgATP and the clinical phenotype.
Functional studies of some of these mutations have suggested that several of them lead to defective interactions in the tubulin heterodimer assembly pathway whereas others may alter TUBA1A three-dimensional conformation and/or compromise its interaction with MAPs or microtubule motors such as kinesin [ 104, 160, 161].
Mutation analysis has suggested that both the N-terminal RING and C-terminal SPRY domains of rhesus TRIM5-alpha contribute to its HIV-1 inhibitory activity, thus the regions that code for these domains were sequenced in TRIM5[ 40].
Previous deletion mutations study has suggested that the GNE kinase domain is responsible for dimerization, while a segment of residues between the epimerase and kinase domains, residues 360 382, is a potential site for trimerization [18].
Analysis of conditional hypomorphic mutations or degron alleles has suggested an order and a function for each gene product in SPB duplication, microtubule nucleation, or other functions such as exit from mitosis.
Previous work in vitro and in vivo has suggested that mutation of the first zinc finger (ZF1) in PARP-1's DBD leads to loss of DNA binding and PARP activation in response to both DNA SSBs and DSBs, while mutation of the 2nd zinc finger (ZF2) leads to a relatively selective loss of response to SSB's [34], [36], [37].
Genome-wide sequencing has suggested certain mutation signatures are associated with specific cancer types (Alexandrov et al., 2013) but lacks the power to identify driver mutations that give rise to that mutation signature.
A recent survey of the structural basis of in-frame mutations in protein-protein interactions has suggested that changes in specific interactions play a critical role in pathogenesis [ 44].
Codon 248 is located in the DNA binding domain and mutations in this specific location has suggested generating a protein incapable of binding to target DNA, thereby losing its regulatory function on transcription [ 33].
