PMID- 25205113
OWN - NLM
STAT- MEDLINE
DCOM- 20150824
LR  - 20240322
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 24
IP  - 1
DP  - 2015 Jan 1
TI  - The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis 
      (INCL) for testing nonsense suppression therapy.
PG  - 185-96
LID - 10.1093/hmg/ddu428 [doi]
AB  - The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a 
      group of autosomal recessive neurodegenerative disorders in children 
      characterized by the progressive onset of seizures, blindness, motor and 
      cognitive decline and premature death. Patients with mutations in CLN1 primarily 
      manifest with infantile NCL (INCL or Haltia-Santavuori disease), which is second 
      only to congenital NCL for its age of onset and devastating progression. CLN1 
      encodes a lysosomal enzyme, palmitoyl-protein thioesterase 1 (PPT1). Nonsense 
      mutations in CLN1 account for 52.3% of all disease causing alleles in infantile 
      NCL, the most common of which worldwide is the p.R151X mutation. Previously, we 
      have shown how nonsense-mediated decay is involved in the degradation of CLN1 
      mRNA transcripts containing the p.R151X mutation in human lymphoblast cell lines. 
      We have also shown how the read-through drugs gentamicin and ataluren (PTC124) 
      increase CLN1 (PPT1) enzyme activity. Here, we provide the initial 
      characterization of the novel Cln1(R151X) mouse model of infantile neuronal 
      ceroid lipofuscinosis that we have generated. This nonsense mutation model 
      recapitulates the molecular, histological and behavioral phenotypes of the human 
      disease. Cln1(R151X) mice showed a significant decrease in Cln1 mRNA level and 
      PPT1 enzyme activity, accumulation of autofluorescent storage material, 
      astrocytosis and microglial activation in the brain. Behavioral characterization 
      of Cln1(R151X) mice at 3 and 5 months of age revealed significant motor deficits 
      as measured by the vertical pole and rotarod tests. We also show how the 
      read-through compound ataluren (PTC124) increases PPT1 enzyme activity and 
      protein level in Cln1(R151X) mice in a proof-of-principle study.
CI  - (c) The Author 2014. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Miller, Jake N
AU  - Miller JN
AD  - Division of Basic Biomedical Sciences, Sanford School of Medicine of the 
      University of South Dakota, Vermillion, SD, USA Sanford Children's Health 
      Research Center, Sanford Research, Sioux Falls, SD, USA and.
FAU - Kovacs, Attila D
AU  - Kovacs AD
AD  - Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD, USA 
      and.
FAU - Pearce, David A
AU  - Pearce DA
AD  - Division of Basic Biomedical Sciences, Sanford School of Medicine of the 
      University of South Dakota, Vermillion, SD, USA Sanford Children's Health 
      Research Center, Sanford Research, Sioux Falls, SD, USA and Department of 
      Pediatrics, Sanford School of Medicine of the University of South Dakota, Sioux 
      Falls, SD, USA david.pearce@sanfordhealth.org.
LA  - eng
GR  - P20 RR024219/RR/NCRR NIH HHS/United States
GR  - 1P20RR024219-01A2/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140908
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Codon, Nonsense)
RN  - 0 (Membrane Proteins)
RN  - 0 (Oxadiazoles)
RN  - 0 (RNA, Messenger)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (PPT1 protein, human)
RN  - K16AME9I3V (ataluren)
SB  - IM
MH  - Animals
MH  - Brain/metabolism/pathology
MH  - Cell Line
MH  - *Codon, Nonsense
MH  - Disease Models, Animal
MH  - Gene Targeting
MH  - Humans
MH  - Infant
MH  - Infant, Newborn
MH  - Male
MH  - Membrane Proteins/*genetics/*metabolism
MH  - Mice
MH  - Neuronal Ceroid-Lipofuscinoses/drug therapy/*genetics/pathology/*physiopathology
MH  - Oxadiazoles/administration & dosage/pharmacology
MH  - Point Mutation
MH  - RNA, Messenger/metabolism
MH  - Thiolester Hydrolases
PMC - PMC4326326
EDAT- 2014/09/11 06:00
MHDA- 2015/08/25 06:00
PMCR- 2016/01/01
CRDT- 2014/09/11 06:00
PHST- 2014/09/11 06:00 [entrez]
PHST- 2014/09/11 06:00 [pubmed]
PHST- 2015/08/25 06:00 [medline]
PHST- 2016/01/01 00:00 [pmc-release]
AID - ddu428 [pii]
AID - 10.1093/hmg/ddu428 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2015 Jan 1;24(1):185-96. doi: 10.1093/hmg/ddu428. Epub 2014 Sep 8.