title: Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits.
abstract: A subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized which has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osmiophilic deposits (GROD). Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211 , Z max = 2.63, straight theta = 0.00). The INCL gene, palmitoyl-protein thioesterase (PPT ; CLN1), was therefore screened for mutations in 11 vJNCL/GROD families. Five mutations in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151STOP. The missense mutation Thr75Pro accounted for nine of the 22 disease chromosomes analysed and the nonsense mutation Arg151STOP for seven. Nine out of 11 patients were shown to combine a missense mutation on one disease chromosome with a nonsense mutation on the other. Mutations previously identified in INCL were not observed in vJNCL/GROD families. Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with controls. These results demonstrate that this subtype of JNCL is allelic to INCL and further emphasize the correlation which exists between genetic basis and ultrastructural changes in the NCLs.
authors.affiliation: Department of Paediatrics, University College London Medical School, The Rayne Institute, 5 University Street, London WC1E 6JJ, UK. hmitchis@ucl.ac.uk
authors.forename: H M
authors.initials: HM
authors.lastname: Mitchison
authors.forename: S L
authors.initials: SL
authors.lastname: Hofmann
authors.forename: C H
authors.initials: CH
authors.lastname: Becerra
authors.forename: P B
authors.initials: PB
authors.lastname: Munroe
authors.forename: B D
authors.initials: BD
authors.lastname: Lake
authors.forename: Y J
authors.initials: YJ
authors.lastname: Crow
authors.forename: J B
authors.initials: JB
authors.lastname: Stephenson
authors.forename: R E
authors.initials: RE
authors.lastname: Williams
authors.forename: I L
authors.initials: IL
authors.lastname: Hofman
authors.forename: P E
authors.initials: PE
authors.lastname: Taschner
authors.forename: J J
authors.initials: JJ
authors.lastname: Martin
authors.forename: M
authors.initials: M
authors.lastname: Philippart
authors.forename: E
authors.initials: E
authors.lastname: Andermann
authors.forename: F
authors.initials: F
authors.lastname: Andermann
authors.forename: S E
authors.initials: SE
authors.lastname: Mole
authors.forename: R M
authors.initials: RM
authors.lastname: Gardiner
authors.forename: A M
authors.initials: AM
authors.lastname: O'Rawe
mesh_terms: D017668:Age of Onset; D000483:Alleles; D002648:Child; D003594:Cytoplasmic Granules / Q000648:ultrastructure; D004252:DNA Mutational Analysis; D005060:Europe / Q000453:epidemiology; D005091:Exons / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D009472:Neuronal Ceroid-Lipofuscinoses / Q000145:classification / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000648:ultrastructure*; D009656:North America / Q000453:epidemiology; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D017422:Sequence Analysis, DNA; D013869:Thiolester Hydrolases / Q000172:deficiency / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase