InterPro domain: IPR003492

Batten's disease, the juvenile variant of neuronal ceroid lipofuscionosis(NCL), is a recessively inherited disorder affecting children of 5-10years of age. The disease is characterised by progressive loss of vision,seizures and psychomotor disturbances. Biochemically, the disease ischaracterised by lysosomal accumulation of hydrophobic material, mainly ATPsynthase subunit C, largely in the brain but also in other tissues. The disease is fatal within a decade [ 1 ].

Mutations in the CLN3 gene are believed to cause Batten's disease [ 2 ]. TheCLN3 gene, with a predicted 438-residue product, maps to chromosome p16p12.1. The gene contains at least 15 exons spanning 15kb and is highly conserved in mammals [ 2 ]. A 1.02kb deletion in the CLN3 gene, occurring in either one or both alleles, is found in 85% of Batten disease chromosomes causing a frameshift generating a predicted translated product of 181 amino acid residues [ 3 , 3 ]. 22 other mutations, including deletions, insertions and point mutations, have beenreported. It has been suggested that such mutations result in severelytruncated CLN3 proteins, or affect its structure/conformation [ 4 , 4 ].

CLN3 proteins, which are believed to associate in complexes, are heavilyglycosylated lysosomal membrane proteins [ 5 ], containing complex Asn-linkedoligosaccharides [ 5 ]. Extensive glycosylation is important for the stabilityof these lysosomal proteins in the highly hydrolytic lysosomal lumen. Lysosomalsequestration of active lysosomal enzymes, transport of degraded moleculesfrom the lysosomes, and fusion and fission between lysosomes and otherorganelles. The CLN3 protein is a 43kDa, highly hydrophobic, multi-transmembrane (TM),phosphorylated protein [ 5 ]. Hydrophobicity analysis predicts 6-9 TMsegments, suggesting that CLN3 is a TM protein that may function as achaperone or signal transducer. The majority of putative phosphorylationsites are found in the N-terminal domain, encompassing 150 residues [ 5 ].Phosphorylation is believed to be important for membrane compartment interaction, in the formation of functional complexes, and in regulation and interactions with other proteins [ 6 ].

CLN3 contains several motifs that may undergo lipid post-translationalmodifications (PTMs). PTMs contribute to targeting and anchoring of modifiedproteins to distinct biological membranes [ 7 ]. There are three general classes of lipid modification: N-terminal myristoylation, C-terminal prenylation, and palmitoylation of cysteine residues. Such modifications are believed to be a common form of PTM occurring in 0.5% of all cellularproteins, including brain tissue [ 8 ]. The C terminus of the CLN3 containsvarious lipid modification sites: C435, target for prenylation; G419, target for myristoylation; and C414, target for palmitoylation [ 9 ].Prenylation results in protein hydrophobicity, influences interaction withupstream regulatory proteins and downstream effectors, facilitates protein-protein interaction (multisubunit assembly) and promotes anchoring tomembrane lipids. The prenylation motif, Cys-A-A-X, is highly conservedwithin CLN3 protein sequences of different species [ 10 ].Species with known CLN3 protein homologues include: Homo sapiens, Canis familiaris, Mus musculus, Saccharomyces cerevisiae and Drosophila melanogaster.

1. Isolation of a novel gene underlying Batten disease, CLN3. The International Batten Disease Consortium. Cell 82, 949-57
2. Characterization and cloning of lgp110, a lysosomal membrane glycoprotein from mouse and rat cells. J. Biol. Chem. 265, 12036-43
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