{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T12:46:52Z","timestamp":1772801212530,"version":"3.50.1"},"reference-count":33,"publisher":"BMJ","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[1998,9]]},"abstract":"<jats:p>The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited degenerative neurological diseases affecting children. A number of non-allelic variants have been identified within the human population and the genes for some of these have recently been identified. The underlying mechanism for the neuropathology remains an enigma; however, pioneering studies with the naturally occurring ovine model (OCL) have led to the proposal that these diseases represent lesions in specific hydrophobic protein degradation pathways. In this study, we show linkage between OCL and microsatellite markers on OAR 7q13-15. Using interspecies chromosome painting we establish that OAR 7q13-15 is syntenic with human chromosome 15q21-23, the region which was recently defined as the location of a newly identified late infantile variant (CLN6). We propose that our ovine model represents a mutation in the gene orthologous to that mutated in the human late infantile variant CLN6. The ovine linkage flock, consisting of 56 families, represents a powerful resource for positional cloning of this NCL gene. The availability of such a large animal model will have important implications for experimentation in downstream corrective therapies.<\/jats:p>","DOI":"10.1136\/jmg.35.9.717","type":"journal-article","created":{"date-parts":[[2008,11,10]],"date-time":"2008-11-10T15:37:21Z","timestamp":1226331441000},"page":"717-721","source":"Crossref","is-referenced-by-count":55,"title":["Ovine neuronal ceroid lipofuscinosis: a large animal model syntenic with the human neuronal ceroid lipofuscinosis variant CLN6."],"prefix":"10.1136","volume":"35","author":[{"given":"M F","family":"Broom","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J E","family":"Broom","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K J","family":"Barwell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R D","family":"Jolly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D F","family":"Hill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[1998,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1055\/s-2007-973655","article-title":"From locus to cellular disturbances: positional cloning of the infantile neuronal ceroid-lipofuscinosis gene","volume":"28","author":"Hellsten, E.; Vesa, J.; Jalanko, A.; Peltonen, L.","year":"1997","unstructured":"Hellsten E, Vesa J, Jalanko A, Peltonen L. From locus to cellular disturbances: positional cloning of the infantile neuronal ceroid-lipofuscinosis gene. Neuropediatrics 1997;28:9-1 1.","journal-title":"Neuropediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1093\/hmg\/6.4.591","article-title":"Loci for classical and a variant late infantile neuronal ceroid lipofuscinosis map to chromosomes llpl5 and 15q21-23","volume":"6","author":"Sharp, J.D.; Wheeler, R.B.; Lake, B.D.","year":"1997","unstructured":"Sharp JD, Wheeler RB, Lake BD, et al. Loci for classical and a variant late infantile neuronal ceroid lipofuscinosis map to chromosomes llpl5 and 15q21-23. 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Cell 1995;82:949-57.","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1006\/geno.1996.0324","article-title":"Efficient construction of a physical map by fibre-fish of the CLN5 region: refined assignment and long range contig covering the critical region on 13q22","volume":"35","author":"Klokars, T.; Savukoski, M.; Isosomppi, J.","year":"1996","unstructured":"Klokars T, Savukoski M, Isosomppi J, et al. Efficient construction of a physical map by fibre-fish of the CLN5 region: refined assignment and long range contig covering the critical region on 13q22. Genomics 1996;35:71-8.","journal-title":"Genomics"},{"key":"ref_6","first-page":"291","article-title":"Mutations in the palmitoyl-protein thioesterase gene (PPT; CLNI) causing juvenile ceroid lipofuscinosis with granular osmiophilic deposits","volume":"7","author":"Mitchison, H.M.; Hofmann, S.L.; Becerra, C.H.R.","year":"1998","unstructured":"Mitchison HM, Hofmann SL, Becerra CHR, et al. Mutations in the palmitoyl-protein thioesterase gene (PPT; CLNI) causing juvenile ceroid lipofuscinosis with granular osmiophilic deposits. Hum Mol Genet 1998;7:291-7.","journal-title":"Hum Mol Genet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1093\/hmg\/6.13.2191","article-title":"Towards an ovine model of cystic fibrosis","volume":"6","author":"Harris, A.","year":"1997","unstructured":"Harris A. Towards an ovine model of cystic fibrosis. Hum Mol Genet 1997;6:2191-3.","journal-title":"Hum Mol Genet"},{"key":"ref_8","first-page":"861","article-title":"Comparative genome mapping in mammals. Curr Opin Genet Dev","volume":"4","author":"Edwards, J.H.","year":"1994","unstructured":"Edwards JH. Comparative genome mapping in mammals. Curr Opin Genet Dev 1994;4:861-7."},{"key":"ref_9","first-page":"1511","article-title":"The SCID mouse: relevance as an animal model system for studying human disease","volume":"143","author":"Hendrickson, E.A.","year":"1993","unstructured":"Hendrickson EA. The SCID mouse: relevance as an animal model system for studying human disease. Am Pathol 1993;143:1511-22.","journal-title":"Am Pathol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1002\/ajmg.1320420436","article-title":"Sheep and other animals with ceroid-lipofuscinoses: their relevance to Batten disease","volume":"42","author":"Jolly, R.D.; Martinus, R.D.; Palmer, D.N.","year":"1992","unstructured":"Jolly RD, Martinus RD, Palmer DN. Sheep and other animals with ceroid-lipofuscinoses: their relevance to Batten disease. Am JMed Genet 1992;42:609-14.","journal-title":"Am JMed Genet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5736","DOI":"10.1016\/S0021-9258(18)83610-9","article-title":"Ovine ceroid lipofuscinosis: the major lipopigment protein and the lipid-binding subunit of mitochondrial ATP synthase have the same NH2-terminal sequence","volume":"264","author":"Palmer, D.; Martinus, R.; Cooper, S.; Midwinter, G.; Reid, J.; Jolly, R.","year":"1989","unstructured":"Palmer D, Martinus R, Cooper S, Midwinter G, Reid J, Jolly R. Ovine ceroid lipofuscinosis: the major lipopigment protein and the lipid-binding subunit of mitochondrial ATP synthase have the same NH2-terminal sequence. Biol Chem 1989;264:5736-40.","journal-title":"Biol Chem"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1042\/bj2680751","article-title":"The sequence of the major protein stored in the ovine ceroid lipofuscinosis is identical with that of the dicyclohexylcarbodiimidereactive proteolipid of mitochondrial ATP synthase","volume":"268","author":"Fearnley, I.M.; Walker, J.E.; Martinus, R.D.","year":"1990","unstructured":"Fearnley IM, Walker JE, Martinus RD, et al. The sequence of the major protein stored in the ovine ceroid lipofuscinosis is identical with that of the dicyclohexylcarbodiimidereactive proteolipid of mitochondrial ATP synthase. BiochemJ 1990;268:751-8.","journal-title":"BiochemJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1055\/s-2007-973670","article-title":"The ovine model of ceroid-lipofuscinosis (NCL): its contribution to understanding the pathogenesis of Batten disease","volume":"28","author":"Jolly, R.D.","year":"1997","unstructured":"Jolly RD. The ovine model of ceroid-lipofuscinosis (NCL): its contribution to understanding the pathogenesis of Batten disease. Neuropediatrics 1997;28:60-2.","journal-title":"Neuropediatrics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/0925-4439(95)00087-9","article-title":"Assembly of mitochondrial ATP synthase in cultured human cells: implications for mitochondrial diseases","volume":"1272","author":"Nijtmans, L.G.J.; Klement, P.; Houstek, J.; van den Bogert, C.","year":"1995","unstructured":"Nijtmans LGJ, Klement P, Houstek J, van den Bogert C. 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Genetics 1995;140:703-24.","journal-title":"Genetics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1007\/BF00661277","article-title":"Resolving ambiguities in the karyotype of domestic sheep (Ovis aries)","volume":"102","author":"Ansari, H.A.; Pearce, P.D.; Maher, D.W.; Malcolm, A.A.; Broad, T.E.","year":"1993","unstructured":"Ansari HA, Pearce PD, Maher DW, Malcolm AA, Broad TE. Resolving ambiguities in the karyotype of domestic sheep (Ovis aries). Chromosoma 1993;102:340-7.","journal-title":"Chromosoma"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1007\/BF00292023","article-title":"Construction of a large-insert yeast artificial chromosome library from sheep DNA","volume":"5","author":"Broom, M.F.; Hill, D.F.","year":"1994","unstructured":"Broom MF, Hill DF. Construction of a large-insert yeast artificial chromosome library from sheep DNA. Mammalian Genome 1994;5:817-19.","journal-title":"Mammalian Genome"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/0888-7543(92)90445-X","article-title":"The development and application of automated gridding for efficient screening of yeast and bacterial ordered libraries","volume":"12","author":"Bentley, D.R.; Todd, C.; Collins, J.","year":"1992","unstructured":"Bentley DR, Todd C, Collins J, et al. The development and application of automated gridding for efficient screening of yeast and bacterial ordered libraries. Genomics 1992;12: 534-41.","journal-title":"Genomics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1159\/000134425","article-title":"Genetic and physical mapping of the ovine cystic fibrosis gene","volume":"74","author":"Tebbutt, S.J.; Broom, M.F.; van Stijn, T.C.; Montgomery, G.W.; Hill, D.F.","year":"1996","unstructured":"Tebbutt SJ, Broom MF, van Stijn TC, Montgomery GW, Hill DF. Genetic and physical mapping of the ovine cystic fibrosis gene. Cytwgenet Cell Genet 1996;74:245-7.","journal-title":"Cytwgenet Cell Genet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1023\/A:1018406120484","article-title":"Isolation of chromosome-specific paints from high-resolution flow karyotype of the sheep (Ovis aries)","volume":"5","author":"Burkin, D.J.; O'Brian, P.C.M.; Broad, T.E.","year":"1997","unstructured":"Burkin DJ, O'Brian PCM, Broad TE, et al. Isolation of chromosome-specific paints from high-resolution flow karyotype of the sheep (Ovis aries). Chrom Res 1997;5: 1-7.","journal-title":"Chrom Res"},{"key":"ref_22","first-page":"2363","article-title":"Construction of multilocus genetic linkage","volume-title":"maps in humans. Proc Natl Acad Sci USA","volume":"84","author":"Lander, E.S.; Green, P.","year":"1987","unstructured":"Lander ES, Green P. Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci USA 1987;84: 2363-7."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s003359900086","article-title":"Comparative analysis of the cattle and human genomes: detection of ZOO-FISH and gene mapping-based chromosomal homologies","volume":"7","author":"Chowdhary, B.P.; Fronicke, L.; Gustavsson, I.; Scherthan, H.","year":"1996","unstructured":"Chowdhary BP, Fronicke L, Gustavsson I, Scherthan H. Comparative analysis of the cattle and human genomes: detection of ZOO-FISH and gene mapping-based chromosomal homologies. Mammalian Genome 1996;7:297-302.","journal-title":"Mammalian Genome"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1006\/geno.1995.1081","article-title":"Comparative genome map of human and cattle","volume":"27","author":"Solinas-Toldo, S.; Lengauer, C.; Fries, R.","year":"1995","unstructured":"Solinas-Toldo S, Lengauer C, Fries R Comparative genome map of human and cattle. Genomics 1995;27:489-96.","journal-title":"Genomics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1159\/000132898","article-title":"International system for cytogenetic nomenclature of domestic animals","volume":"53","author":"DiBerardino, D.; Hayes, H.; Fries, R.; Long, S.","year":"1989","unstructured":"DiBerardino D, Hayes H, Fries R, Long S. International system for cytogenetic nomenclature of domestic animals (1989). Cytogenet Cell Genet 1990;53:65-79.","journal-title":"Cytogenet Cell Genet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1159\/000134429","article-title":"Standardization of cattle karyotype nomenclature: report of the committee for the standardization of the cattle karyotype","volume":"74","author":"Popescu, C.P.; Long, S.; Riggs, P.","year":"1996","unstructured":"Popescu CP, Long S, Riggs P, et al. Standardization of cattle karyotype nomenclature: report of the committee for the standardization of the cattle karyotype. Cytogenet Cell Genet 1996;74:259-61.","journal-title":"Cytogenet Cell Genet"},{"key":"ref_27","first-page":"826","article-title":"Chromosomal mapping of the bovine aromatase gene (cypl9) and an aromatase pseudogene to chromosome 10 and syntenic group U5","volume-title":"Mammalian Genome","volume":"5","author":"Goldammer, T.; Guerin, G.; Brunner, R.M.; Vanselow, J.; Furbass, R.; Schwerin, M.","year":"1994","unstructured":"Goldammer T, Guerin G, Brunner RM, Vanselow J, Furbass R, Schwerin M. Chromosomal mapping of the bovine aromatase gene (cypl9) and an aromatase pseudogene to chromosome 10 and syntenic group U5. Mammalian Genome 1994;5:826-7."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1111\/j.1365-2052.1995.tb02668.x","article-title":"Sheep gene mapping: assignment of ALDOB, CYP19, WT and SOX2 by somatic cell hybrid analysis","volume":"26","author":"Payen, E.; Saidi-Mehtar, N.; Pailhoux, E.; Cotinot, C.","year":"1995","unstructured":"Payen E, Saidi-Mehtar N, Pailhoux E, Cotinot C. Sheep gene mapping: assignment of ALDOB, CYP19, WT and SOX2 by somatic cell hybrid analysis. Animal Genet 1995; 26:331-3.","journal-title":"Animal Genet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1055\/s-2007-973666","article-title":"Different patterns of hydrophobic protein storage in different forms of neuronal ceroid-lipofuscinosis (NCL, Batten disease)","volume":"28","author":"Palmer, D.N.; Jolly, R.D.; van Mil, H.C.; Tyynela, J.; Westlake, V.J.","year":"1997","unstructured":"Palmer DN, Jolly RD, van Mil HC, Tyynela J, Westlake VJ. Different patterns of hydrophobic protein storage in different forms of neuronal ceroid-lipofuscinosis (NCL, Batten disease). Neuropediatrics 1997;28:45-8.","journal-title":"Neuropediatrics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/978-1-4899-5339-1_15","article-title":"Lysosomal storage of the DCCD reactive proteolipid subunit of mitochondrial ATP synthase in human and ovine ceroid lipofuscinoses","volume-title":"ceroid pigments. Vol 1","author":"Palmer, D.N.; Fearnley, I.M.; Medd, S.M.","year":"1990","unstructured":"Palmer DN, Fearnley IM, Medd SM, et al. Lysosomal storage of the DCCD reactive proteolipid subunit of mitochondrial ATP synthase in human and ovine ceroid lipofuscinoses. In: Porta EA, ed. Lipofuscin and ceroid pigments. Vol 1. New York: Plenum Press, 1990:211-23."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1097\/00005072-199704000-00005","article-title":"Variant late infantile ceroid-lipofuscinosis: patholmorphology and biochemistry","volume":"56","author":"Tyynela, J.; Suopanki, J.; Santavuori, P.; Baumann, M.; Haitia, M.","year":"1997","unstructured":"Tyynela J, Suopanki J, Santavuori P, Baumann M, Haitia M. Variant late infantile ceroid-lipofuscinosis: patholmorphology and biochemistry. J Neuropathol Exp Neurol 1997;56: 369-75.","journal-title":"J Neuropathol Exp Neurol"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/ajmg.1320570214","article-title":"Immunocytochemical studies in the ceroid-lipofuscinoses (Batten disease) using antibodies to subunit c of the mitochondrial ATP synthase","volume":"57","author":"Westlake, V.J.; Jolly, R.D.; Bayliss, S.L.; Palmer, D.N.","year":"1995","unstructured":"Westlake VJ, Jolly RD, Bayliss SL, Palmer DN. Immunocytochemical studies in the ceroid-lipofuscinoses (Batten disease) using antibodies to subunit c of the mitochondrial ATP synthase. Am J Med Genet 1995;57:177-81.","journal-title":"Am J Med Genet"},{"key":"ref_33","article-title":"Molecular genetic analysis of a variant form of Batten disease with granular osmiophilic deposits. Sixth International Congress on Neuronal Ceroid-Lipofuscinoses, Gustavelund","author":"O'Rawe, A.M.; Mitchison, H.M.; Williams, R.","year":"17.","unstructured":"O'Rawe AM, Mitchison HM, Williams R, et al. Molecular genetic analysis of a variant form of Batten disease with granular osmiophilic deposits. Sixth International Congress on Neuronal Ceroid-Lipofuscinoses, Gustavelund, Finland, 1996:Abstract 17."}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg.35.9.717","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T04:21:56Z","timestamp":1759724516000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg.35.9.717"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,9]]},"references-count":33,"journal-issue":{"issue":"9","published-online":{"date-parts":[[1998,9,1]]},"published-print":{"date-parts":[[1998,9]]}},"alternative-id":["10.1136\/jmg.35.9.717"],"URL":"https:\/\/doi.org\/10.1136\/jmg.35.9.717","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,9]]}}}