| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T1 |
0-167 |
Sentence |
denotes |
A Pro504 --> Ser substitution in the beta-subunit of beta-hexosaminidase A inhibits alpha-subunit hydrolysis of GM2 ganglioside, resulting in chronic Sandhoff disease. |
| T2 |
168-421 |
Sentence |
denotes |
The GM2 gangliosidoses are caused by mutations in the genes encoding the alpha- (Tay-Sachs) or beta- (Sandhoff) subunits of heterodimeric beta-hexosaminidase A (Hex A), or the GM2 activator protein (AB variant), a substrate-specific co-factor for Hex A. |
| T3 |
422-658 |
Sentence |
denotes |
Although the active site associated with the hydrolysis of GM2 ganglioside, as well as part of the binding site for the ganglioside-activator complex, is associated with the alpha-subunit, elements of the beta-subunit are also involved. |
| T4 |
659-788 |
Sentence |
denotes |
Missense mutations in these genes normally result in the mutant protein being retained in the endoplasmic reticulum and degraded. |
| T5 |
789-922 |
Sentence |
denotes |
The mutations associated with the B1-variant of Tay-Sachs are rare exceptions that directly affect residues in the alpha-active site. |
| T6 |
923-1051 |
Sentence |
denotes |
We have previously reported two sisters with chronic Sandhoff disease who were heterozygous for the common HEXB deletion allele. |
| T7 |
1052-1180 |
Sentence |
denotes |
Cells from these patients had higher than expected levels of mature beta-protein and residual Hex A activity, approximately 20%. |
| T8 |
1181-1301 |
Sentence |
denotes |
We now identify these patients' second mutant allele as a C1510T transition encoding a beta-Pro504 --> Ser substitution. |
| T9 |
1302-1743 |
Sentence |
denotes |
Biochemical characterization of Hex A from both patient cells and cotransfected CHO cells demonstrated that this substitution (a) decreases the level of heterodimer transport out of the endoplasmic reticulum by approximately 45%, (b) lowers its heat stability, (c) does not affect its Km for neutral or charged artificial substrates, and (d) lowers the ratio of units of ganglioside/units of artificial substrate hydrolyzed by a factor of 3. |
| T10 |
1744-1902 |
Sentence |
denotes |
We concluded that the beta-Pro504 --> Ser mutation directly affects the ability of Hex A to hydrolyze its natural substrate but not its artificial substrates. |
| T11 |
1903-2044 |
Sentence |
denotes |
The effect of the mutation on ganglioside hydrolysis, combined with its effect on intracellular transport, produces chronic Sandhoff disease. |
