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The CLN3 Gene and Protein: What We Know

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The CLN3 Gene and Protein: What We Know Received: 9 August 2018 | Revised: 30 May 2019 | Accepted: 31 May 2019 DOI: 10.1002/mgg3.859 REVIEW ARTICLE The CLN3 gene and protein: What we know Myriam Mirza1 | Anna Vainshtein2 | Alberto DiRonza3,4 | Uma Chandrachud5 | Luke J. Haslett6 | Michela Palmieri3,4 | Stephan Storch7 | Janos Groh8 | Niv Dobzinski9 | Gennaro Napolitano10 | Carolin Schmidtke7 | Danielle M. Kerkovich11 1Mila’s Miracle Foundation, Boulder, Colorado Abstract 2Craft Science Inc., Thornhill, Canada Background: One of the most important steps taken by Beyond Batten Disease 3Baylor College of Medicine, Houston, Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the Texas State of the Science. We believe that a strong understanding of where we are in our 4 Jan and Dan Duncan Neurological experimental understanding of the CLN3 gene, its regulation, gene product, protein Research Institute at Texas Children’s Hospital, Houston, Texas structure, tissue distribution, biomarker use, and pathological responses to its defi- 5Center for Genomic Medicine, ciency, lays the groundwork for determining therapeutic action plans. Massachusetts General Hospital/Harvard Objectives: To present an unbiased comprehensive reference tool of the experimen- Medical School, Boston, Massachusetts tal understanding of the CLN3 gene and gene product of the same name. 6School of Biosciences, Cardiff University, BBDF compiled all of the available CLN3 gene and protein data from Cardiff, UK Methods: 7Biochemistry, University Medical Center biological databases, repositories of federally and privately funded projects, patent Hamburg‐Eppendorf, Hamburg, Germany and trademark offices, science and technology journals, industrial drug and pipeline 8Neurology, University Hospital reports as well as clinical trial reports and with painstaking precision, validated the Wuerzburg, Wuerzburg, Germany information together with experts in Batten disease, lysosomal storage disease, lyso- 9Biochemistry and Biophysics, UCSF some/endosome biology. School of Medicine, San Francisco, California Results: The finished product is an indexed review of the CLN3 gene and protein 10Telethon Institute of Genetics and which is not limited in page size or number of references, references all available Medicine, Napoli, Italy primary experiments, and does not draw conclusions for the reader. 11Beyond Batten Disease Foundation, Conclusions: Revisiting the experimental history of a target gene and its product Austin, Texas ensures that inaccuracies and contradictions come to light, long‐held beliefs and as- Correspondence sumptions continue to be challenged, and information that was previously deemed Danielle M. Kerkovich, Principal Scientist, inconsequential gets a second look. Compiling the information into one manuscript Beyond Batten Disease Foundation, P.O. Box 50221, Austin, TX 78763. with all appropriate primary references provides quick clues to which studies have Email: [email protected] been completed under which conditions and what information has been reported. This compendium does not seek to replace original articles or subtopic reviews but Funding information Beyond Batten Disease Foundation provides an historical roadmap to completed works. KEYWORDS Batten, CLN3, JNCL, juvenile Batten, neuronal ceroid lipofuscinosis This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Mol Genet Genomic Med. 2019;7:e859. wileyonlinelibrary.com/journal/mgg3 | 1 of 41 https://doi.org/10.1002/mgg3.859 2 of 41 | MIRZA ET AL. 1 | INTRODUCTION distribution, co‐regulated gene expression, biomarker use, and pathological responses to CLN3 protein deficiencies in Basic knowledge of the expression, regulation, structure, yeast through humans. Supplementary materials include a list and function transmembrane‐bound and other proteins, en- of CLN3 research tools and their associated first‐published ables the discovery of compounds to modulate their behavior. reports. Along with analyses of disease‐causing mutations, investiga- The authors note that following data extraction from the tors pursue creative approaches to restore protein function(s) information systems mentioned above, the information gath- and their associated pathways. Therefore, it is critically im- ered here was verified and the associated primary literature portant that academicians, pharmaceutical investigators, and was cited along with the experimental methods used. We clinician scientists, be provided with a complete, easy‐to‐ believe bioinformatics databases such as those mentioned access, and an up‐to‐date State of the Science. Historically, above offer scientists the opportunity to access and cross‐ref- one relied on review articles designed to summarize current erence a wide variety of biologically relevant data providing thinking. However, an information explosion fueled by ad- new insights and further means to validate their discoveries. vances in molecular biology, genetic engineering, and new However, the authors would like to stress that the databases animal models, coupled with competing hypotheses of au- listed here were used only to provide a framework for the thors and size limits of review articles has resulted in the pro- document. The rapid release of new data from various –omics duction of irregular, nonsystematic review articles in disease and other programs annotated using computational analysis research leading to unintentional bias and widening knowl- sometimes leads to misinformation, which we found to be edge gaps. To combat this problem, investigators new to the the case for the CLN3 gene and protein. Therefore, the au- field must spend hundreds of hours sifting, reading, and eval- thors worked to provide their readership with direct access to uating original publications; defeating the purpose for which primary, experimentally proven data. Finally, the authors dil- review articles were created. igently tried to avoid summarizing the information herein in Beyond Batten Disease Foundation (BBDF) has taken support of one hypothesis over another or drawing any con- a lead to help support new and existing researchers in their clusions for the reader. This comprehensive agnostic presen- quest for experimentally proven, unbiased, information. This tation of experimental findings is meant to complement and manuscript is part of a larger strategic plan to advance re- not overlap investigator‐driven primary and review literature. search in Batten disease by fueling the creation of key physi- cal and informational resources. The foundation worked with Thomson Reuters to gather referenced CLN3 gene and CLN3 2 | GENERAL INFORMATION protein information and with painstaking attention to detail, CLN3 validated the information together with experts in CLN3 dis- 2.1 | Description of the gene ease, lysosomal storage disease, and lysosome/endosome bi- The official name of this gene is “ceroid‐lipofuscinosis, neu- ology. The resultant indexed review of CLN3 and CLN3 is ronal 3” and official symbol is CLN3. Less commonly used not limited in size, focuses on information from original arti- terms include BATTENIN, BTS, JNCL (Juvenile Neuronal cles, is reviewed by in‐area experts and inclusion in validated Ceroid Lipofuscinosis), and MGC102840. CLN3 was dis- databases, and does not draw conclusions. By collecting all covered using linkage analysis in search for the disease of the available information into a single, searchable refer- causing gene (mutation) in 48 children with progressive vi- ence manual, this review saves valuable time and ensures all sion loss, seizures, decline of intellect and loss of motor abil- topic areas are covered; however, readers will still need to ity (Eiberg, Gardiner, & Mohr, 1989). Researchers found a review original literature cited here. linkage between CLN3 disease and haptoglobin (140100) on The information found within this reference tool is cul- chromosome 16q22 revealing the location of the CLN3 gene tivated by: (a) MetaBase™ (version 6.20), a systems biol- (Eiberg et al., 1989; Gardiner et al., 1990). Linkage studies ogy database, a former product of GeneGo, IntegritySM, (b) in larger groups of families followed by physical mapping of a drug and pipeline information database, Cortellis™, and markers by mouse/human hybrid cell analysis and fluores- (c) a drug and clinical trial information database, Thomson cence in situ hybridization refined the coordinates of CLN3 Innovation™, including patent information from around the to the interval between D16S288 and D16S298 (see Figure world and public databases (December 2014 version), such as 1: LinkageMapping, (Callen et al., 1991, 1992; Järvelä, NCBI, Ensembl, dbSNP, UniProt, MGI and others. The infor- Mitchison, Callen, et al., 1995; Järvelä, Mitchison, O'rawe, et mation cultivated from these databases was then traced back al., 1995; Lerner et al., 1994; Mitchison, O'Rawe, Lerner, et al., its original source and rigorously reviewed. If the experiment 1995; Mitchison, O’Rawe, Taschner, et al., 1995; Mitchison was conducted more than once, all references were added. et al., 1994; Mitchison, Williams, et al., 1993; Mitchison, The manual includes a research history of the CLN3 Thompson, et al., 1993) The final pieces of the puzzle were gene, discussion of gene regulation, protein structure, tissue
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