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2013 ANCL Mole

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Mole Laboratory: Adult Batten Disease

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2013 ANCL Mole

  1. 1. 3 Mole Laboratory:Mole Laboratory: Adult Batten DiseaseAdult Batten Disease Sara Mole, Michael Bond, Mariana Vieira, Davide Marotta, Sophia kleine Holthaus, Charlotte Ridler, Varun Warrier, Rachel BrownSara Mole, Michael Bond, Mariana Vieira, Davide Marotta, Sophia kleine Holthaus, Charlotte Ridler, Varun Warrier, Rachel Brown MRC Laboratory for Molecular Cell Biology, University College London, London, UK, WC1E 6BT, s.mole@ucl.ac.ukMRC Laboratory for Molecular Cell Biology, University College London, London, UK, WC1E 6BT, s.mole@ucl.ac.uk INTRODUCTION (Laboratory Objectives)  The cause of most cases of adult onset NCL until recently has not been known. We have been collecting cases (DNA and cell lines) for many years and built up a large resource of adult onset NCL (recessive and dominant). We have been analysing these cases for mild mutations in genes that normally cause childhood onset NCL. Mutations in several childhood NCL genes can cause adult NCL. In families that appear to have disease caused by mutations in novel genes we are using the powerful new DNA sequencing technologies to identify new genes. 4 Key Projects What this means For Therapy 9 Diagnostic algorithms guide gene testing and help to reach a genetic diagnosis Summary table of NCL genes with adult onset cases highlighted. Some are new genes that have been identified collaboratively using the outlined strategy Acknowledgements: 1. It is very hard to develop a new therapy for a disease where the cause is not known. 2. Identifying the genes causing disease in such families is the first step. 3. Once a gene is identified, what it does normally, and what is going wrong in the disease can be studied. 4. This information will help in the development of targeted therapy. 5. There are not many families with adult Batten disease. We therefore collaborate with other laboratories around the world to identify these genes. 6. We also use the same approach for any family with Batten disease that is not genetically defined. Function Therapy Mutations Disease Genes Models Gene symbol Protein Diseases Soluble lysosomal enzyme deficiencies CTSD CLN10 Cathepsin D CLN10 disease, congenital CLN10 disease, late infantile CLN10 disease, juvenile CLN10 disease, adult PPT1 CLN1 Palmitoyl protein thioesterase 1, PPT1 CLN1 disease, infantile CLN1 disease, late infantile CLN1 disease, juvenile CLN1 disease, adult TPP1 CLN2 Tripeptidyl peptidase 1, TPP1 CLN2 disease, late infantile CLN2 disease, juvenile CTSF CLN13 Cathepsin F CLN13 disease, adult Kufs type B Non-enzyme deficiencies, (functionsof identified proteins generally poorly understood at the current time) CLN3 Transmembrane protein CLN3 disease, juvenile CLN5 Soluble; lysosomal CLN5 disease, late infantile CLN5 disease, juvenile CLN5 disease, adult CLN6 Transmembrane protein; ER CLN6 disease, late infantile CLN6 disease, adult Kufs type A MFSD8 CLN7 Major facilitator superfamily domain-containing protein 8 Transmembrane protein; Endolysosomal transporter CLN7 disease, late infantile CLN8 Transmembrane protein; ER, ER-Golgi intermediate complex CLN8 disease, late infantile CLN8 disease, EPMR DNAJC5 CLN4 Soluble cysteine string protein α CLN4 disease, adult autosomal dominant GRN CLN11 Progranulin CLN11 disease, adult Heterozygous mutations cause frontotemporal lobar dementia ATP13A2 CLN12 P-type ATPase CLN12 disease, juvenile Mutations also cause Kufor-Rakeb syndrome KCTD7 CLN14 Potassium channel tetramerization domain- containing protein 7 CLN14 disease, infantile Mutation also causes progressive myoclonic epilepsy-3 Others: those whose classification is uncertain because of incomplete diagnostic investigationsor absence of confirmed gene/mutation designation, or where NCLisa rare or minor mutation- specificphenotype ? Mutations not yet defined in any gene Congenital/infantile variants ? Mutations not yet defined in any gene Late infantile variants ?CLN9? Mutations not yet defined in any gene Juvenile variants ? Mutations not yet defined in any gene Late onset/adult variants including some adult Kufs type B CLCN6 Mutations not yet found on both disease alleles in human disease Chloride transport defect, adult onset SGSH Mutations usually cause MPSIIIA Adult onset Family Sample Database Clinical details; EM Pathology, Lymphocyte vacuoles; Enzyme results; Sequencing analysis Diagnosis of NCL suspected Sequence known NCL genes NCL Enzyme tests New gene identification Linkage, exome sequencing CLN1, CLN2 or CLN10 disease CLN1, CLN2 or CLN10 mutations CLN3, CLN5, CLN6, CLN7, CLN8 mutations Mutation analysis of CLN? in existing cohorts Schema of approach to identify new genes

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