PMID- 10332042
OWN - NLM
STAT- MEDLINE
DCOM- 19990708
LR  - 20190513
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 8
IP  - 6
DP  - 1999 Jun
TI  - Defective intracellular transport of CLN3 is the molecular basis of Batten
      disease (JNCL)
PG  - 1091-8
AB  - Batten disease [juvenile-onset neuronal ceroid lipofuscinosis (JNCL)], the most
      common progressive encephalopathy of childhood, is caused by mutations in a novel
      lysosomal membrane protein (CLN3) with unknown function. In this study, we have
      confirmed the lysosomal localization of the CLN3 protein by immunoelectron
      microscopy by co-localizing it with soluble and membrane-associated lysosomal
      proteins. We have analysed the intracellular processing and localization of two
      mutants, 461-677del, which is present in 85% of CLN3 alleles and causes the
      classical JNCL, and E295K [corrected], which is a rare missense mutation
      associated with an atypical form of JNCL. Pulse-chase labelling and
      immunoprecipitation of the two mutant proteins in COS-1-cells indicated that
      461-677del is synthesized as an approximately 24 kDa truncated polypeptide,
      whereas the maturation of E295K [corrected] resembles that of the wild-type CLN3 
      polypeptide. Transient expression of the two mutants in BHK cells showed that
      461-677del is retained in the endoplasmic reticulum, whereas E295K [corrected]
      was capable of reaching the lysosomal compartment. The CLN3 polypeptides were
      expressed further in mouse primary neurons where the wild-type CLN3 protein was
      localized both in the cell soma and in neuronal extensions, whereas the
      461-677del mutant was arrested in the cell soma. Interestingly, co-localization
      of the wild-type CLN3 and E295K [corrected] proteins with a synaptic vesicle
      marker indicates that the CLN3 protein might participate in synaptic vesicle
      transport/transmission. The data presented here provide clear evidence for a
      cellular distinction between classical and atypical forms of Batten disease both 
      in neural and non-neural cells.
FAU - Jarvela, I
AU  - Jarvela I
AD  - National Public Health Institute, Laboratory of Human Molecular Genetics,
      Helsinki, Finland. irma.jarvela@ktl.fi
FAU - Lehtovirta, M
AU  - Lehtovirta M
FAU - Tikkanen, R
AU  - Tikkanen R
FAU - Kyttala, A
AU  - Kyttala A
FAU - Jalanko, A
AU  - Jalanko A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (CLN3 protein, human)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Proteins)
RN  - 0 (Recombinant Fusion Proteins)
SB  - IM
EIN - Hum Mol Genet 1999 Aug;8(8):1585
MH  - Amino Acid Substitution
MH  - Animals
MH  - Biological Transport/genetics
MH  - COS Cells
MH  - Cell Line
MH  - Eukaryotic Cells/cytology/metabolism/ultrastructure
MH  - Female
MH  - Fluorescent Antibody Technique
MH  - Humans
MH  - *Membrane Glycoproteins
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microscopy, Immunoelectron
MH  - *Molecular Chaperones
MH  - Mutation
MH  - Neuronal Ceroid-Lipofuscinoses/*genetics
MH  - Neurons/metabolism
MH  - Pregnancy
MH  - Proteins/*genetics/metabolism
MH  - Recombinant Fusion Proteins/genetics
MH  - Sequence Deletion
MH  - Telencephalon/cytology
MH  - Transfection
EDAT- 1999/05/20 00:00
MHDA- 1999/05/20 00:01
CRDT- 1999/05/20 00:00
PHST- 1999/05/20 00:00 [pubmed]
PHST- 1999/05/20 00:01 [medline]
PHST- 1999/05/20 00:00 [entrez]
AID - ddc118 [pii]
AID - 10.1093/hmg/8.6.1091 [doi]
PST - ppublish
SO  - Hum Mol Genet. 1999 Jun;8(6):1091-8. doi: 10.1093/hmg/8.6.1091.