In contrast, CLN3, the gene for juvenile NCL (Batten or Spielmeyer-Vogt-Sjögren disease) is not a previously known gene, nor does its product display homology to any previously described proteins.
CLN3 is an endosomal/lysosomal transmembrane protein mutated in classical juvenile onset neuronal ceroid lipofuscinosis, a fatal inherited neurodegenerative lysosomal storage disorder.
In this family, the patient and one of the healthy siblings have identical haplotypes, excluding linkage of early juvenile NCL to the CLN3 locus on 16p12.1-11.2.
To identify candidate biomarkers, we analyzed autopsy brain and matching CSF samples from controls and three genetically distinct NCLs due to deficiencies in palmitoyl protein thioesterase 1 (CLN1 disease), tripeptidyl peptidase 1 (CLN2 disease), and CLN3 protein (CLN3 disease).
We have examined mRNA levels of the CLN1, CLN2, and CLN3 genes, which are associated with the infantile, late infantile, and juvenile forms of NCL in 64 different human tissues, and have grouped the results into gastrointestinal tract, central nervous system, glandular/secretory, muscle, and carcinoma tissue types. mRNA levels for CLN3 are highest in gastrointestinal tissue and are also high in glandular/secretory tissue, whereas mRNA levels for CLN1 and CLN2 do not appear to be preferentially elevated in any tissue type.
Using a metabolomics approach based on high resolution 1H NMR spectroscopy of the cortex, cerebellum, and remaining regions of the brain in conjunction with statistical pattern recognition, we report metabolic deficits associated with juvenile NCL in a Cln3 knock-out mouse model.
Herein, we report that three NCL disease forms with similar tissue pathology are connected at the molecular level: CLN5 polypeptides directly interact with the CLN2 and CLN3 proteins based on coimmunoprecipitation and in vitro binding assays.
There are a number of clinically and genetically distinct forms of ceroid-lipofuscinosis, the most common of which is the juvenile type, also known as Batten disease and CLN3.