MUTATIONS IN THE PALMITOYL-PROTEIN THIOESTERASE GENE (PPT, CLN1) CAUSING JUVENILE NEURONAL CEROID-LIPOFUSCINOSIS WITH GRANULAR OSMIOPHILIC DEPOSITS

A subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized w hich has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osm iophilic deposits (GROD), Evidence supporting linkage of this phenotyp e, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was de monstrated (pairwise lod score with D1S211, Z(max) = 2.63, theta = 0.0 0), The INCL gene, palmitoyl-protein thioesterase (PPT; CLN1), was the refore screened for mutations in 11 vJNCL/GROD families, Five mutation s in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151 STOP, The missense mutation Thr75Pro accounted for nine of the 22 dise ase chromosomes analysed and the nonsense mutation Arg151STOP for seve n, Nine out of 11 patients were shown to combine a missense mutation o n one disease chromosome with a nonsense mutation on the other. Mutati ons previously identified in INCL were not observed in vJNCL/GROD fami lies, Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with cont rols, These results demonstrate that this subtype of JNCL is allelic t o INCL and further emphasize the correlation which exists between gene tic basis and ultrastructural changes in the NCLs.