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.

Impaired autophagy: The collateral damage of lysosomal storage disorders

“…The most commonly found defect (a founder mutation) is a homozygous deletion of 966 base pairs inclusive of exons 7 and 8 (Δex7/8) which results in a premature stop codon in exon 9 of the 15-exon gene [49] . The promoter of the CLN3 gene contains CLEAR elements which makes it a part of the TFEB-regulated gene network [ 13 , 14 ], thus opening a possibility of TFEB modulation as a therapeutic approach to Batten disease [50] .…”

The c.1A > C start codon mutation in CLN3 is associated with a protracted disease course

“…However, whether this tightly controlled regulatory process also applies to a variant in the start codon is speculative. In addition to transcriptional (regulatory) processes as described above, also, other—genetic, such as post‐translational modifications, and probably non‐genetic—modifying factors could impact residual CLN3 protein synthesis and function . Regardless of the exact underlying mechanism, the protracted phenotype displayed by all three patients discussed in this report strongly indicates that the c.1A > C start codon variant in CLN3 allows some degree of residual protein synthesis.…”

“…2 The milder phenotype could not be explained by the 1 kb deletion on the other allele, as this common founder mutation severely affects CLN3 protein synthesis generally hypothesized to completely abolish CLN3 protein function. 5,6 Indeed, although some degree of phenotypic heterogeneity is seen, homozygosity for the 1 kb deletion-present in around 75% of CLN3 disease patients-is consequently associated with the classical phenotype. 2,5,7,8 In this report, we assessed the hypothesis that the c.1A > C variant in CLN3 is responsible for a protracted CLN3 disease phenotype by successfully searching for additional patients harboring this genotype and delineating their disease course.…”

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

“…Three full KO models of Cln3 have thus far been established all displaying hallmarks of CLN3 such as progressive neurodegeneration (Mitchison et al, 1999;Cotman et al, 2002;Eliason et al, 2007). To date there has been research using these models in alleviating CLN3 pathology with administration of various antiinflammatory and neuroprotective compounds such as ibuprofen and lamotrigine to modulate intracellular inflammatory conditions (Mirza et al, 2019;Tarczyluk-Wells et al, 2019). 4.…”