Title : Characterization of the mechanisms by which missense mutations in the lysosomal acid lipase gene disrupt enzymatic activity - Vinje_2019_Hum.Mol.Genet_28_3043
Author(s) : Vinje T , Laerdahl JK , Bjune K , Leren TP , Strom TB
Ref : Hum Mol Genet , 28 :3043 , 2019
Abstract :

Hydrolysis of cholesteryl esters and triglycerides in the lysosome is performed by lysosomal acid lipase (LAL). In this study we have investigated how 23 previously identified missense mutations in the LAL gene (LIPA) (OMIM# 613497) affect the structure of the protein and thereby disrupt LAL activity. Moreover, we have performed transfection studies to study intracellular transport of the 23 mutants. Our main finding was that most pathogenic mutations result in defective enzyme activity by affecting the normal folding of LAL. Whereas, most of the mutations leading to reduced stability of the cap domain did not alter intracellular transport, nearly all mutations that affect the stability of the core domain gave rise to a protein that was not efficiently transported from the endoplasmic reticulum (ER) to the Golgi apparatus. As a consequence, ER stress was generated that is assumed to result in ER-associated degradation of the mutant proteins. The two LAL mutants Q85K and S289C were selected to study whether secretion-defective mutants could be rescued from ER-associated degradation by the use of chemical chaperones. Of the five chemical chaperones tested, only the proteasomal inhibitor MG132 markedly increased the amount of mutant LAL secreted. However, essentially no increased enzymatic activity was observed in the media. These data indicate that the use of chemical chaperones to promote the exit of folding-defective LAL mutants from the ER, may not have a great therapeutic potential as long as these mutants appear to remain enzymatically inactive.

PubMedSearch : Vinje_2019_Hum.Mol.Genet_28_3043
PubMedID: 31131398
Gene_locus related to this paper: human-LIPA

Related information

Mutation L264P_human-LIPA    Q85K_human-LIPA    N98K_human-LIPA    G342W_human-LIPA    G342R_human-LIPA    Q298H_human-LIPA    T288I_human-LIPA    Q85R_human-LIPA    Q87V_human-LIPA    W95R_human-LIPA    R127W_human-LIPA    D145E_human-LIPA    P202L_human-LIPA    R276K_human-LIPA    I391S_human-LIPA    L294S_human-LIPA    H295Y_human-LIPA    L357P_human-LIPA    S289C_human-LIPA    N119S_human-LIPA    H129P_human-LIPA    H129R_human-LIPA    L200P_human-LIPA
Gene_locus L264P_human-LIPA    Q85K_human-LIPA    N98K_human-LIPA    G342W_human-LIPA    G342R_human-LIPA    Q298H_human-LIPA    T288I_human-LIPA    Q85R_human-LIPA    Q87V_human-LIPA    W95R_human-LIPA    R127W_human-LIPA    D145E_human-LIPA    P202L_human-LIPA    R276K_human-LIPA    I391S_human-LIPA    L294S_human-LIPA    H295Y_human-LIPA    L357P_human-LIPA    S289C_human-LIPA    N119S_human-LIPA    H129P_human-LIPA    H129R_human-LIPA    L200P_human-LIPA    human-LIPA
Disease L264P_human-LIPA    Q85K_human-LIPA    N98K_human-LIPA    G342W_human-LIPA    G342R_human-LIPA    Q298H_human-LIPA    T288I_human-LIPA    Q85R_human-LIPA    Q87V_human-LIPA    W95R_human-LIPA    R127W_human-LIPA    D145E_human-LIPA    P202L_human-LIPA    R276K_human-LIPA    I391S_human-LIPA    L294S_human-LIPA    H295Y_human-LIPA    L357P_human-LIPA    S289C_human-LIPA    N119S_human-LIPA    H129P_human-LIPA    H129R_human-LIPA    L200P_human-LIPA    human-LIPA    Wolman disease WD, Cholesterol Ester Storage Disease, CESD

Citations formats

Vinje T, Laerdahl JK, Bjune K, Leren TP, Strom TB (2019)
Characterization of the mechanisms by which missense mutations in the lysosomal acid lipase gene disrupt enzymatic activity
Hum Mol Genet 28 :3043

Vinje T, Laerdahl JK, Bjune K, Leren TP, Strom TB (2019)
Hum Mol Genet 28 :3043