PMID- 21704547
OWN - NLM
STAT- MEDLINE
DCOM- 20120228
LR  - 20211020
IS  - 1096-7206 (Electronic)
IS  - 1096-7192 (Print)
IS  - 1096-7192 (Linking)
VI  - 104
IP  - 3
DP  - 2011 Nov
TI  - Stop codon read-through with PTC124 induces palmitoyl-protein thioesterase-1 
      activity, reduces thioester load and suppresses apoptosis in cultured cells from 
      INCL patients.
PG  - 338-45
LID - 10.1016/j.ymgme.2011.05.021 [doi]
AB  - Infantile neuronal ceroid lipofuscinosis (INCL), a lethal hereditary 
      neurodegenerative lysosomal storage disorder, affects mostly children. It is 
      caused by inactivating mutations in the palmitoyl-protein thioesterase-1(PPT1) 
      gene. Nonsense mutations in a gene generate premature termination codons 
      producing truncated,nonfunctional or deleterious proteins. PPT1 
      nonsense-mutations account for approximately 31% of INCL patients in the US. 
      Currently, there is no effective treatment for this disease. While 
      aminoglycosides such asgentamycin suppress nonsense mutations, inherent toxicity 
      of aminoglycosides prohibits chronic use inpatients. PTC124 is a non-toxic 
      compound that induces ribosomal read-through of premature termination codons. We 
      sought to determine whether PTC124-treatment of cultured cells from INCL patients 
      carrying nonsense mutations in the PPT1 gene would correct PPT1 enzyme-deficiency 
      with beneficial effects. Our results showed that PTC124-treatment of cultured 
      cells from INCL patients carrying PPT1 nonsense-mutations induced PPT1 enzymatic 
      activity in a dose- and time-dependent manner. This low level of PPT1 enzyme 
      activity induced by PTC124 is virtually identical to that induced by 
      gentamycin-treatment. Even though only a modest increase in PPT1 activity was 
      achieved by PTC124-treatment of INCL cells, this treatment reduced the levels of 
      thioester (constituent of ceroid) load. Our results suggest that PTC124-treatment 
      induces PPT1 enzymatic activity in cultured cells from INCL patients carrying 
      PPT1 nonsense-mutations, and this modest enzymatic activity has demonstrable 
      beneficial effects on these cells. The clinical relevance of these effects may be 
      tested in animal models of INCL carrying nonsense mutations in the PPT1 gene.
FAU - Sarkar, Chinmoy
AU  - Sarkar C
AD  - Section on Developmental Genetics, Program on Developmental Endocrinology and 
      Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human 
      Development, National Institutes of Health, Bethesda, MD 20892-1830, USA.
FAU - Zhang, Zhongjian
AU  - Zhang Z
FAU - Mukherjee, Anil B
AU  - Mukherjee AB
LA  - eng
GR  - Z99 HD999999/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20110613
PL  - United States
TA  - Mol Genet Metab
JT  - Molecular genetics and metabolism
JID - 9805456
RN  - 0 (Codon, Nonsense)
RN  - 0 (Codon, Terminator)
RN  - 0 (Membrane Proteins)
RN  - 0 (Oxadiazoles)
RN  - 0 (Tetrazolium Salts)
RN  - 0 (Thiazoles)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (PPT1 protein, human)
RN  - EUY85H477I (thiazolyl blue)
RN  - K16AME9I3V (ataluren)
SB  - IM
MH  - Apoptosis/*drug effects
MH  - Cells, Cultured
MH  - Chromatography, Thin Layer
MH  - Codon, Nonsense/genetics
MH  - Codon, Terminator/*drug effects
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Induction/drug effects
MH  - Fluorescent Antibody Technique
MH  - Humans
MH  - Membrane Proteins/*biosynthesis/*genetics/metabolism
MH  - Microscopy, Electron, Transmission
MH  - Neuronal Ceroid-Lipofuscinoses/*drug therapy/genetics/*physiopathology
MH  - Oxadiazoles/*pharmacology
MH  - Tetrazolium Salts
MH  - Thiazoles
MH  - Thiolester Hydrolases
MH  - Time Factors
PMC - PMC3220191
MID - NIHMS305421
COIS- Conflict of Interest The authors declare no conflict of interest.
EDAT- 2011/06/28 06:00
MHDA- 2012/03/01 06:00
PMCR- 2012/11/01
CRDT- 2011/06/28 06:00
PHST- 2011/04/08 00:00 [received]
PHST- 2011/05/13 00:00 [revised]
PHST- 2011/05/13 00:00 [accepted]
PHST- 2011/06/28 06:00 [entrez]
PHST- 2011/06/28 06:00 [pubmed]
PHST- 2012/03/01 06:00 [medline]
PHST- 2012/11/01 00:00 [pmc-release]
AID - S1096-7192(11)00192-2 [pii]
AID - 10.1016/j.ymgme.2011.05.021 [doi]
PST - ppublish
SO  - Mol Genet Metab. 2011 Nov;104(3):338-45. doi: 10.1016/j.ymgme.2011.05.021. Epub 
      2011 Jun 13.