Value of predictive bioinformatics in inherited metabolic diseases

Table 1 Examples of freely available, online tools for predicting the properties of variant proteins

Category	Name	Weblink	Ref.
Structural analysis	YASARA energy minimisation	http://www.yasara.org/minimizationserver.htm	[29]
	LS-SNP	ls-snp.icm.jhu.edu/ls-snp-pdb/main	[30]
	GETAREA	curie.utmb.edu/getarea.html	[31]
Stability prediction	I-Mutant 3.0	gpcr2.biocomp.unibo.it/cgi/predictors/I-Mutant3.0/I-Mutant3.0.cgi	[32,33]
	mCSM	bleoberis.bioc.cam.ac.uk/mcsm/	[34]
	SDM score	mordred.bioc.cam.ac.uk/~sdm/sdm.php	[35,36]
	Mupro	mupro.proteomics.ics.uci.edu	[37]
	iStable	predictor.nchu.edu.tw/iStable/	[38]
	PredictSNP 1.0	loschmidt.chemi.muni.cz/predictsnp/	[39]
	Meta-SNP	snps.biofold.org/meta-snp/	[40]
	KD4V	decrypthon.igbmc.fr/kd4v	[41]
	Fold-X	foldx.crg.es	[42]
	PoPMuSiC	dezyme.com/	[43]
	CUPSAT	cupsat.tu-bs.de	[44,45]
	GETAREA	curie.utmb.edu/getarea.html	[31]
Binding affinity changes	BeAtMuSiC	babylone.ulb.ac.be/beatmusic	[46]
Aggregation tendency, amyloid formation and chaperone binding	TANGO	tango.crg.es/	[47]
	WALTZ	http://www.switchlab.org/bioinformatics/waltz	[48]
	LIMBO	http://www.switchlab.org/bioinformatics/limbo	[49]
Sequence conservation	Clustal Omega	http://www.ebi.ac.uk/tools/msa/clustalo/	[50]
	Scorecons	http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/valdar/scorecons_server.pl	[51]
	SIFT	sift.jcvi.org/	[52]
	PROVEAN	provean.jcvi.org/index.php	[53]
	LS-SNP	ls-snp.icm.jhu.edu/ls-snp-pdb/	[30]
	SNPs and GO	snps.biofold.org/snps-and-go/pages/help.html	[54]
	PANTHER	http://www.pantherdb.org/tools/csnpscoreform.jsp	[55]
	GenMAPP	http://www.genmapp.org	[56]
	PolyPhen 2	genetics.bwh.harvard.edu/pph2/	[57,58]
	nsSNP Analyzer	snpanalyzer.uthsc.edu	[59]
	FI mutation assessor	mutationassessor.org/v1	[60]
	YALE MU2A	krauthammerlab.med.yale.edu/mu2a	[61]

Table 2 Examples of bioinformatics based predictions of the severity of variants associated with inherited metabolic diseases

Disease	Protein	Comments	Ref.
Alkaptonuria	Homogentisate 1,2-dioxygenase	Combining a variety of computational approaches gave rise to the most accurate predictions	[62]
Apparent mineralocorticoid excess	11βHSD2	The predicted degree of structural change in the enzyme correlates with disease severity	[63]
Fabry disease	GLA	A purpose built program designed to detect protein instability outperformed existing, generic tools	[64]
Fabry disease	GLA	A purpose built web interface allows prediction of a patient’s responsiveness to pharmacological chaperone therapy	[65]
Gaucher disease	GBA	Slightly different results were obtained with different programs; however, 22 out of 47 variants were predicted to be harmful by all seven programs used	[28]
Glucose 6-phosphate dehydrogenase deficiency	G6PDH	A combination of prediction tools suggested that protein stability is an important factor in this disease; novel potentially disease-associated variants were identified	[66]
Hyperargininemia	ARG1	Mutations affect residues in the active site, or protein stability, or quaternary structure	[67]
MODY 2	GCK	Variations which decrease protein stability and/or occur in highly conserved regions of the protein are associated with disease	[68]
Niemann-pick disease type C	NPC1 and NPC2	The majority of disease-associated variants were predicted to be less stable than wild-type	[69]
Phenylketonuria	PAH	Protein stability predicted to be most important factor in disease causation	[10]
Pyruvate kinase deficiency	PK1 and PK2	A combination of prediction tools suggested that protein stability is an important factor in this disease; novel potentially disease-associated variants were identified	[66]
Type I galactosemia	GALT	Main predicted effect is the loss of stability of GALT	[70]
Type III galactosemia	GALE	Effects on protein stability and degree of sequence conservation combined were required for good predictions	[71]

11βHSD2: 11β-hydroxysteroid dehydrogenase type 2; GLA: α-galactosidase A; GBA: Glucocerebrosidase; G6PDH: Glucose 6-phosphate dehydrogenase; ARG1: Arginase 1; GCK: Glucokinase; PAH: Phenylalanine hydroxylase; PK1 and PK2: Pyruvate kinase isoforms 1 and 2; GALT: Galactose 1-phosphate uridylyltransferase; GALE: UDP-galactose 4’-epimerase; MODY 2: Maturity-onset diabetes of the young, type 2.