Neuronal Ceroid Lipofuscinosis

Our group working on neuronal ceroid lipofuscinosis (NCL) consists of:

Dr. Peter Taschner: group leader
Drs. Gert de Voer: Ph.D. student
Ing. Paola van der Bent: technician

Introduction

The neuronal ceroid lipofuscinoses (NCL) are worldwide the most common lysosomal storage disorders of childhood. Clinical features often include progressive visual impairment, seizures, psychomotor deterioration, dementia, and a premature death. Most NCL cases are caused by mutations in the CLN1, CLN2 and CLN3 genes, which play an essential role in lysosomal protein degradation.

Our initial NCL research started in 1992 and concentrated on the genetic analysis of families suffering from juvenile NCL. These studies have resulted in the identification of the CLN3 gene and the development of reliable molecular diagnostics for juvenile NCL. The molecular diagnostics was later extended to include the other forms of NCL and transferred to our Clinical Molecular Genetics Laboratory. Currently, our research focuses on the development and use of Caenorhabditis elegans model systems for NCL.

The nematode Caenorhabditis elegans as a model for NCL.

We are using C. elegans as a model for juvenile NCL in particular. This simple worm has three genes homologous to human CLN3: cln-3.1, cln-3.2, and cln-3.3. Deletion mutants for each have been obtained and all mutations have been combined in the same background. The viability of the cln-3 triple mutant demonstrates that these genes are not essential for normal development and function. Detailed characterization of the triple mutant, particularly in relation to a possible neuronal specific function, is in progress.

Student Projects

Students may participate in the development and application of tools for one of the following topics:

Currently none available

For more information please contact Peter Taschner

Relevant links

Caenorhabditis elegans links

NCL Publications

De Voer G, Van der Bent P, Rodrigues AJG, Van Ommen GJB, Peters DJM, Taschner PEM. Deletion of the Caenorhabditis elegans homologues of the CLN3 gene, involved in human Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), causes a mild progeric phenotype. J Inherit Metab Dis, in press.

Taschner PEM, Losekoot M, Breuning MH, Hofman I, van Diggelen OP (2005). Van gen naar ziekte; van CLN1, CLN2 en CLN3 naar neuronale ceroid lipofuscinose. (From gene to disease; from CLN1, CLN2 and CLN3 to neuronal ceroid lipofuscinosis.) Ned Tijdschr Geneesk 149: 300-303.

Mole SE, Zhong NA, Sarpong A, Logan WP, Hofmann S, Yi W, Franken PF, van Diggelen OP, Breuning MH, Moroziewicz D, Ju W, Salonen T, Holmberg V, Jarvela I, Taschner PEM (2001). New mutations in the neuronal ceroid lipofuscinosis genes. Europ J Paediatr Neurol 5 Suppl A: 7-10.

De Voer G, Jansen G, van Ommen GJ, Peters DJ, Taschner PEM (2001). Caenorhabditis elegans homologues of the CLN3 gene, mutated in juvenile neuronal ceroid lipofuscinosis. Europ J Paediatr Neurol 5 Suppl A: 115-120.

Van Diggelen OP, Thobois S, Tilikete C, Zabot MT, Keulemans JL, van Bunderen PA, Taschner PEM, Losekoot M, Voznyi YV (2001). Adult neuronal ceroid lipofuscinosis with palmitoyl-protein thioesterase deficiency: first adult-onset patients of a childhood disease. Ann Neurol 50: 269-272.

Mitchison HM, Bernard DJ, Greene ND, Cooper JD, Junaid MA, Pullarkat RK, de Vos N, Breuning MH, Owens JW, Mobley WC, Gardiner RM, Lake BD, Taschner PEM, Nussbaum RL (1999) Targeted disruption of the Cln3 gene provides a mouse model for Batten disease. Neurobiol Dis 6: 321-334

De Vries BB, Kleijer WJ, Keulemans JL, Voznyi YV, Franken PF, Eurlings MC, Galjaard RJ, Losekoot M, Catsman-Berrevoets CE, Breuning MH, Taschner PEM, van Diggelen OP (1999) First-trimester diagnosis of infantile neuronal ceroid lipofuscinosis (INCL) using PPT enzyme assay and CLN1 mutation analysis. Prenat Diagn 19: 559-562

Hofman I, Kohlschütter A, Santavuori P, Gottlob I, Goebel HH, Lake BD, Schutgens RBH, Greene NDE, Leung K-Y, Mitchison HM, Munroe PB, Taschner PEM (1999) CLN3 - Juvenile NCL, p. 55-76. In: Goebel HH, Mole SE, Lake BD (Eds.) The neuronal ceroid lipofuscinoses (Batten disease). Biomedical and Health Research 33. IOS Press, Amsterdam.

Martin J-J, Ceuterick C, Elleder M, Kraus J, Nevsimalova S, Sixtova K, Zeman J, Santavuori P, Chabrol B, Kohlschütter A, Lake BD, Christomanou H, Cardona F, Nardocci N, Kmiec T, Pineda M, Mila M, Ferrer I, Navarro C, Uvebrant P, Hofman I, Taschner PEM, Williams RE, Topçu, Çaliskan M (1999) NCL in different European countries, p. 128-141. In: Goebel HH, Mole SE, Lake BD (Eds.) The neuronal ceroid lipofuscinoses (Batten disease). Biomedical and Health Research 33. IOS Press, Amsterdam.

Taschner PEM, Franken PF, van Berkel L, Breuning MH (1999) Genetic heterogeneity of neuronal ceroid lipofuscinosis in The Netherlands. Mol Genet Metab 66: 339-343

Greene ND, Bernard DL, Taschner PEM, Lake BD, de Vos N, Breuning MH, Gardiner RM, Mole SE, Nussbaum RL, Mitchison HM (1999) A murine model for juvenile NCL: gene targeting of mouse Cln3. Mol Genet Metab 66: 309-313

Stephenson JB, Greene ND, Leung KY, Munroe PB, Mole SE, Gardiner RM, Taschner PEM, O'Regan M, Naismith K, Crow YJ, Mitchison HM (1999) The molecular basis of GROD-storing neuronal ceroid lipofuscinoses in Scotland. Mol Genet Metab 66: 245-247

Mitchison HM, Hofmann, SL, Becerra CHR, Munroe PB, Lake BD, Crow YJ, Stephenson JBP, Williams RE, Hofman IL, Taschner PEM, Martin JJ, Phillippart M, Andermann E, Andermann F, Mole SE, Gardiner RM, O'Rawe AM (1998) Mutations in the palmitoyl-protein thioesterase gene (PPT;CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. Hum Mol Genet 7: 291-297

Mitchison HM, Munroe PB, O'Rawe AM, Taschner PEM, de Vos N, Kremmidiotis G, Lensink I, Munk AC, D'Arigo KL, Anderson JW, Lerner TJ, Moyzis RK, Callen DF, Breuning MH, Doggett NA, Gardiner RM, Mole SE (1997) Genomic structure and complete nucleotide sequence of the Batten disease gene, CLN3. Genomics 40: 346-350

Taschner PEM, de Vos N, Breuning MH (1997) Cross species homology of the CLN3 gene. Neuropediatrics 28: 18-20.

Taschner PEM, de Vos N, Breuning MH (1997) Rapid detection of the major deletion in the Batten disease gene CLN3 by allele specific PCR. J Med Genet 34: 955-956

Mitchison HM, Taschner PEM, Kremmidiotis G, Callen DF, Doggett NA, Lerner TJ, Janes RB, Wallace BA, Munroe PB, O'Rawe AM, Gardiner RM, Mole SE (1997) Structure of the CLN3 gene and predicted structure, location and function of CLN3 protein. Neuropediatrics 28: 12-14.

Munroe PB, Mitchison HM, O'Rawe AM, Anderson JW, Boustany R MN, Lerner TJ, Taschner PEM, de Vos N, Breuning MH, Gardiner RM, Mole SE (1997) Spectrum of mutations in the Batten disease gene, CLN3. Am J Hum Genet 61: 310-316.

Munroe PB, O'Rawe AM, Mitchison HM, Jarvela I, Santavuori P, Lerner TJ, Taschner PEM, Gardiner RM, Mole SE (1997) Strategy for mutation detection in CLN3: characterisation of two Finnish mutations. Neuropediatrics 28: 15-17.

The International Batten Disease Consortium: Lerner TJ, Boustany R-MN, Anderson JW, D'Arigo KL, Schlumpf K, Buckler AJ, Gusella JF, Haines JL; Kremmidiotis G, Lensink IL, Sutherland GR, Callen DF; Taschner PEM, De Vos N, Van Ommen G-JB, Breuning MH; Doggett NA, Meincke LJ, Liu Z-Y, Goodwin LA, Tesmer JG; Mitchison HM, O'Rawe A, Munroe PB, Järvelä IE, Gardiner RM, Mole SE (1995) Isolation of a novel gene underlying Batten disease, CLN3. Cell 82: 949-957.

Taschner PEM, de Vos N, Thompson AD, Callen DF, Doggett N, Mole SE, Dooley TP, Barth PG, Breuning MH (1995) Chromosome 16 microdeletion in a patient with juvenile neuronal ceroid lipofuscinosis (Batten disease). Am J Hum Genet 56: 663-668.

Taschner PEM, de Vos N, Catsman Berrevoets CE, van Duinen SG, Lindhout D, Breuning MH (1995) Application of chromosome 16 markers in the differential diagnosis of neuronal ceroid lipofuscinosis. Am J Med Genet 57: 338- 343.

Taschner PEM, de Vos N, Post JG, Meijers Heijboer EJ, Hofman I, Pinckers AJLG, Bleeker Wagemakers EM, Gardiner RM, Breuning MH (1995) Carrier detection of Batten disease (juvenile neuronal ceroid lipofuscinosis). Am J Med Genet 57: 333-337.

Hofman IL, Taschner PEM (1995) Late onset juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits (GROD). Am J Med Genet 57: 165-167.

Järvelä IE, Mitchison HM, Callen DF, Lerner TJ, Doggett NA, Taschner PEM, Gardiner RM, Mole SE (1995) Physical map of the region containing the gene for Batten disease (CLN3). Am J Med Genet 57: 316-319.

Järvelä IE, Mitchison HM, O'Rawe AM, Munroe PB, Taschner PEM, de Vos N, Lerner TJ, D'Arigo KL, Callen DF, Thompson AD, Knight M, Marrone BL, Mundt MO, Meincke L, Breuning MH, Gardiner RM, Doggett NA, Mole SE (1995) YAC and cosmid contigs spanning the Batten disease (CLN3) region at 16p12.1 p11.2. Genomics 29: 478-489.

Lerner TJ, D'Arigo KL, Haines JL, Doggett NA, Taschner PEM, de Vos N, Buckler AJ, Batten Disease Consortium (1995) Isolation of genes form the Batten candidate region using exon amplification. Am J Med Genet 57: 320-323.

Mitchison HM, O'Rawe AM, Lerner TJ, Taschner PEM, Schlumpf K, D'Arigo K, de Vos N, Gormally E, Phillips HA, Thompson AD, Haines JL, Hart YM, Andermann E, Callen DF, Breuning MH, Gardiner RM, Mole SE (1995) Refined localization of the Batten disease gene (CLN3) by haplotype and linkage disequilibrium mapping to D16S288 D16S16S383 and exclusion from this region of a variant form of Batten disease with granular osmiophilic deposits. Am J Med Genet 57: 312-315.

Mitchison HM, O'Rawe AM, Taschner PEM, Sandkuijl LA, Santavuori P, de Vos N, Breuning MH, Mole SE, Gardiner RM, Järvelä I (1995) Batten disease gene, CLN3: linkage disequilibrium mapping in the Finnish population, and analysis of European haplotypes. Am J Hum Genet 56: 654-662.

Mitchison HM, Taschner PEM, O'Rawe AM, de Vos N, Phillips HA, Thompson AD, Kozman HM, Haines JL, Schlumpf K, D'Arigo K, Boustany R MN, Callen DF, Breuning MH, Gardiner RM, Mole SE, Lerner TJ (1994) Genetic mapping of the Batten disease locus (CLN3) to the interval D16S288 D16S383 by analysis of haplotypes and allelic association. Genomics 22: 465-468.

If you have any comments or questions, please contact us! mailto:p.taschner@lumc.nl