Table 3.

Most common single amino-acid substitutions in acid-β-glucosidase that cause Gaucher disease

Mutation	Phenotype	Features	Enzyme activity	Structural features
N370S	Mild	70% of mutant alleles in Ashkenazi Jews; invariably predisposes to mild (type 1) disease	Reduced activity; stable protein	Located on longest helix in protein (helix 7), at interface of domains II and III. Several other mutations are found on this helix (see Fig. 5)
V394L	Severe	–	Reduced activity; stable protein	Near aromatic residues that line one side of the active-site pocket; may disrupt this lining and, therefore, catalytic activity
D409H	Severe	–	Greatly reduced activity; unstable protein	Located on domain I, suggesting it is a regulatory or structural domain
L444P	Severe	Most common mutation that predisposes to severe (types 2 and 3) disease	Reduced activity; unstable protein	Hydrophobic core of Ig-like domain (domain II), which may lead to protein instability due to disruption of the hydrophobic core and altered folding of this domain
R463C	Mild	–	Reduced activity; stable protein	Located on Ig-like domain, distant from the active site
R496H	Mild	–	–	Located on Ig-like domain, distant from the active site

For references about the mutations, see Beutler & Grabowski (2001). Ig, immunoglobulin.