The CLN3 gene and protein: What we know

Abstract

Background: One of the most important steps taken by Beyond Batten Disease Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the State of the Science. We believe that a strong understanding of where we are in our experimental understanding of the CLN3 gene, its regulation, gene product, protein structure, tissue distribution, biomarker use, and pathological responses to its deficiency, lays the groundwork for determining therapeutic action plans.

Objectives: To present an unbiased comprehensive reference tool of the experimental understanding of the CLN3 gene and gene product of the same name.

Methods: BBDF compiled all of the available CLN3 gene and protein data from biological databases, repositories of federally and privately funded projects, patent and trademark offices, science and technology journals, industrial drug and pipeline reports as well as clinical trial reports and with painstaking precision, validated the information together with experts in Batten disease, lysosomal storage disease, lysosome/endosome biology.

Results: The finished product is an indexed review of the CLN3 gene and protein which is not limited in page size or number of references, references all available primary experiments, and does not draw conclusions for the reader.

Conclusions: Revisiting the experimental history of a target gene and its product ensures that inaccuracies and contradictions come to light, long-held beliefs and assumptions continue to be challenged, and information that was previously deemed inconsequential gets a second look. Compiling the information into one manuscript with all appropriate primary references provides quick clues to which studies have been completed under which conditions and what information has been reported. This compendium does not seek to replace original articles or subtopic reviews but provides an historical roadmap to completed works.

Keywords: Batten; CLN3; JNCL; juvenile Batten; neuronal ceroid lipofuscinosis.

Figure 1

Linkage Mapping. The location of the gene responsible for JNCL was mapped to a region on chromosome 16. Initial findings placed the gene on the long arm of chromosome 16, due to its linkage with the haptoglobin (HP) locus. Later, the location of CLN3 was narrowed down to markers tagging the 16p11.2 region. The dinucleotide marker D16S298 is located in an intron of the CLN3 gene and thus represents the true location of CLN3

Figure 2

2a and 2b: 2a Schematic model for human CLN3 showing the six transmembrane helices, proposed amphipathic helix and experimentally determined loop locations. 2b The predicted topology of CLN3 is depicted. Sites for post‐translational modifications are shown as blue forked lines for N‐glycosylation, zigzags for prenylation, and dotted lines for potential cleavage sites following prenylation. Disease‐causing mutations are colored in red, orange, yellow, green, blue, and violet. If the mutation covers multiple residues, only the first residue is marked. (NB‐All disease‐causing mutations are not shown. For a completes list see Table 1)

Figure 3

Lysosomal targeting motifs of CLN3

Figure 4

Tissue expression profile of CLN3 across dataset E‐MTAB‐62 (human)NCBI GEO GSE2361

Figure 5

Tissue expression of CLN3 across NCBI GEO data set GSE10246 (mouse)

Figure 6

Tissue expression of CLN3 across NCBI GEO data set GSE5396 (rat)

Figure 7

Expression of CLN3 in human tissues according to the NCBI GEO GSE1133 data set

Figure 8

Expression of CLN3 in human tissues according to the NCBI GEO GSE7307 data set

Figure 9

Expression of CLN3 in human tissues according to the Gene Atlas data set (Su et al., 2004; Wu et al., 2009)

Figure 10

Cross species tissue expression for top ten tissues by expression level in human

Figure 11

Network diagram of CLN3 interactors. These interactions have been found by ChIP‐chip and Chip‐Seq analysis (Transcription factors binding CLN3 promoter), Microarray analysis (Dysregulated CLN3 expression) and Mass spectrometry analysis (CLN3 PTMs). The majority of these interactions require further validation