Value of predictive bioinformatics in inherited metabolic diseases

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.