Phenotology of disease-linked proteins

Abstract

Are there analogous sequence positions in families of related proteins where disease-linked mutations occur with unusually high frequency? We attempt to answer this question by examining sequence alignments for G-protein coupled receptors (GPCRs) and voltage-gated potassium channels that have a significant number of missense mutations linked to some form of human disease. When the disease-linked mutations are mapped onto the sequences for each family, there are a large number of aligned sites at which disease-linked mutations occur in more than one protein. The statistical significance of the aligned sites is judged by analysis of artificially-generated random datasets. There are a modest number of aligned sites that are statistically significant-we refer to these as "phenotologous" sequence positions. Phenotologous sites represent aligned positions at which mutations linked to disease phenotypes occur with high frequency within a family of proteins. The most interesting of these sites are those which are not conserved-such sites are apparently critical in defining structural or functional differences between related proteins. Phenotology may be used to make experimentally testable predictions regarding medical genetics, the molecular basis of disease, and protein structure-function relationships.

Defining the blanks – Pharmacochaperoning of SLC6 transporters and ABC transporters

“…A similar clustering of disease-linked mutations has been observed for G-protein coupled receptors [84], suggesting that mutations in protein families occur in structurally similar or even identical positions. These positions are prone to result in malfunction, which is rooted in the common fold (molecular architecture) of the protein family.…”

“…Only secondary to this underlying fold-determined cause of disease is the associated phenotype, which is determined by the physiological role that the individual member of the protein family plays. The word “phenotologous sites” or “disease phenotology” has been suggested by the group of Sanders to signify this circumstance [84]. (ii) Active site compounds rescue folding deficient mutants in the a-helical domain of the NBDs.…”

Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations

“…There is a pressing need to develop general methods to quantitatively compare the stabilities of WT and disease mutant forms of these proteins. It is also interesting to note that some of the mutation sites associated with the destabilization of KCNQ1 correspond via homology to known disease mutation sites in other voltage-gated ion channels (39)(40)(41), including a number of KCNQ2 and KCNQ3 sites for which mutations are associated with benign familial neonatal seizures and epileptic encephalopathy (see http://www.hgmd.cf.ac.uk). This suggests that mutationinduced destabilization of protein folding is likely a very common underlying mechanism for many other channelopathies.…”

Mechanisms of KCNQ1 Channel Dysfunction in Long QT Syndrome Involving Voltage Sensor Domain Mutations

“…There is a pressing need to develop general methods to quantitatively compare the stabilities of WT and disease mutant forms of these proteins. It is also interesting to note that some of the mutation sites associated with destabilization of KCNQ1 correspond via homology to known disease mutation sites in other voltage-gated ion channels (39)(40)(41), including a number of KCNQ2 and KCNQ3 sites for which mutations are associated with benign familial neonatal seizures and epileptic encephalopathy (see http://www.hgmd.cf.ac.uk). This suggests that mutation-induced destabilization of protein folding is likely a very common underlying mechanism for many other channelopathies.…”