Table 2.
Missense mutations identified in the α-subunits and β-subunits of Hex A
| Location in α-subunit | Mutation(s) | Structural Phenotype | Cellular phenotype | Clinical phenoype |
|---|---|---|---|---|
| Domain I | L127F,R | Disruption of B-sheet | Na, decreased mRNA | Acute |
| Domain II, at interface between domain I | R166G | Salt bridge lost | Na | Severe subacute |
| Domain II Tim-barrel | R170W,Q | Over packing of residues and disruption of β-sheet | Na | Acute |
| Domain II, active site | R178C,H,L | Over packing of residues disruption of active site | ER retention | Acute |
| Domain II, Tim-barrel | V192L | Over packing of residues and disruption of β-sheet | Targeting mutant, only pro-α generated | Acute |
| Domain II, Tim-barrel | V200M | Over packing of residues and disruption of β-sheet | Targeting mutant, only pro-α generated | Acute |
| Domain II, Tim-barrel | H204R | Over packing of residues and disruption of β-sheet | Na | Acute |
| Domain II, helix at end of Tim-barrel | S210F | Over packing of residues and disruption of β-sheet | Na | Acute |
| Domain II, helix at end of Tim-barrel | F211S | Hydrophobic cavity decreased | Na | Acute |
| Domain II, helix at end of Tim-barrel | D258H | Hydrogen bonding lost and disruption of β-sheet | B1-like activity and targeting mutant | Severe subacute |
| Helical extension of domain II | S279P | Disruption of hydrogen bonding and loop that interacts with the GM2AP | Na | Severe subacute |
| Outer helix of Tim-barrel | M301R | Hydrophobic interaction decreased, buried polar residue | Na | Acute |
| Outer helix of Tim-barrel | F304 | Hydrophobic interaction decreased, buried polar residue | Targeting mutant, only proα generated | Acute |
| Outer helix of Tim-barrel | F305 | Hydrophobic interaction decreased, buried polar residue | Targeting mutant, only proα generated | Acute |
| Domain II, Tim-barrel | G320 | Na | Na | Severe subacute |
| Domain II, Tim-barrel | G321 | Na | Na | Acute |
| Domain II, Tim-barrel | Y420C | Hydrophobic interaction decreased, buried polar residue | No activity, targeting mutation | Acute |
| Domain II, Tim-barrel | G454S,D | Overpacking, backbone strain and disruption of β-sheet | Processing and targeting mutation | Acute |
| Domain II, Tim-barrel | G455R | Overpacking, backbone strain and disruption of β-sheet | Processing and targeting mutation | Acute |
| Domain II, Tim-barrel | C458Y | Overpacking, backbone strain and disruption of β-sheet | No activity | Acute |
| Domain II, Tim-barrel | W474C | Hydrophobic interaction decreased, buried polar residue | Decreased activity, targeting mutation | Acute |
| Domain II, Tim-barrel | E482K | Salt bridge lost | No activity, ER targeting mutation | Acute |
| Domain II, Tim-barrel | L484P | Hydrophobic interaction decreased | No activity, ER targeting mutation | Acute |
| Domain II, Tim-barrel | W485R | Hydrophobic interaction decreased, buried polar residue | No activity, ER targeting mutation | Acute |
| Domain II, Tim-barrel | R499C,H | Salt bridge lost | Decreased activity, targeting mutation | Acute |
| Domain II, Tim-barrel | R504C,H | Salt bridge lost | Decreased activity, targeting mutation | Acute |
| Domain II, Tim-barrel | G250D | Overpacking, buried polar residue | Reduced to Intermediate activity | Subacute |
| Domain II, Tim-barrel | C180H | Decrease hydrophobic interaction | Unstable protein | Chronic |
| Domain II, Tim-barrel | L197T | Salt bridge lost | Na | Chronic |
| Domain II, Tim-barrel | R252H | Hydrogen bonding lost | Na | Chronic |
| Domain II, Tim-barrel | G269S | Overpacking, backbone disortion | Reduced activity | Chronic |
| Domain II, Tim-barrel | V391M | Overpacking | Na | Chronic |
| Domain II, Tim-barrel | R247Y | Salt bridge lost with domain I, Overpacking | Reduced activity, HexA formed but unstable | Asymptomatic |
| Domain II, Tim-barrel | 249 | Salt bridge lost with domain I, Overpacking | Reduced activity, HexA formed but unstable | Asymptomatic |
| Domain II, Tim-barrel | S226F | Overpacking | Na | Uncharacterized |
| Domain II, Tim-barrel | G269D | Overpacking, backbone disortion | Na | Uncharacterized |
| Domain II, Tim-barrel | D314V | Salt bridge lost | Na | Uncharacterized |
| Domain II, extra helix in Tim-barrel | I335F | Overpacking | Na | Uncharacterized |
| Domain I | S62L | No apparent effect | Na | Acute |
| Domain II, Tim-barrel | S255R | Overpacking, buried charged residue | Na | Acute |
| Domain II, Tim-barrel | C534Y | Overpacking, buried hyrophobic residue | Na | Acute |
| Domain II, Tim-barrel | I207V | Decrease in hydrophobic pocket | Neutral polymorphism | Chronic |
| Domain II, in contact with the α-subunit | Y456S | Decrease in hydrophobic pocket | Targeting mutant | Chronic |
| Domain II, Tim-barrel | P504S | Disrupt in backbone | ER retention | Chronic |
| Domain II, Tim-barrel | R505Q | Salt bridge and hydrogen bonding lost | Heat labile HexB | Chronic |
| Domain II, Tim-barrel | A543T | overpacking | Heat labile HexB | Chronic |
Missense mutations identified in the α-subunit and β-subunits of Hex A are listed according to their severity for Tay-Sachs and Sandhoff disease. The color of the text corresponds to the mutations mapped on the structure shown in Figure 6. na: not assessed. References for each individual mutation can be found at http://www.hexdb.mcgill.ca/.2