Human Molecular Genetics, Vol 7, 291-297, Copyright © 1998 by Oxford University Press
HM Mitchison, SL Hofmann, CH Becerra, PB Munroe, BD Lake, YJ Crow, JB Stephenson, RE Williams, IL Hofman, PEM Taschner, JJ Martin, M Philippart, E Andermann, F Andermann, SE Mole, RM Gardiner and AM O'Rawe
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.
ARTICLES
Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits [published erratum appears in Hum Mol Genet 1998 Apr;7(4):765]
Department of Paediatrics, University College London Medical School, The Rayne Institute, 5 University Street, London WC1E 6JJ, UK. hmitchis@ucl.ac.uk
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