Detection of eight novel palmitoyl protein thioesterase (PPT) mutations underlying infantile neuronal ceroid lipofuscinosis (INCL;CLN1)

The infantile form of neuronal ceroid lipofuscinosis (INCL; CLN1) is the ea rliest onset form of the neuronal ceroid lipofuscinoses (NCL), a group of p rogressive encephalopathies of children. INCL is caused by mutations in the palmitoyl protein thioesterase (PPT) gene, and we report here eight novel INCL. mutations in PPT. Five of the mutations, c.456C>A, c.162-163insA, c.1 74-175delG, c.774-775insA, and a splice acceptor mutation IVS1-2A>G in intr on 1, caused the generation of a premature STOP codon either directly or af ter a frameshift, One mutation was a three-bp insertion in exon 2 (c.132-13 3insTGT) leading to insertion of one extra cysteine (Ser44-insCys-Cys45), a nd another mutation, a 3 bp deletion in exon 3 (c.249-251delCTT), led to de letion of Phe84 in PPT A splice acceptor mutation IVS6-1G>T in intron 6 can be predicted to cause skipping of exon 7 in PPT All of these novel mutatio ns were associated with the classical phenotype of INCL, with the first sym ptoms starting around 12 months of age, The severe phenotypes could be expl ained by the nature of the novel mutations: five are predicted to lead to p remature translational termination, thus abolishing the active site of PPT and three will probably cause a misfolding of the nascent polypeptide. Thir ty-five percent (7/20) of the disease alleles in these 11 families containe d the most prevalent c.451C>T missense mutation outside Finland [Das et al, , 1998], Consequently, 31 different mutations underlying INCL have been fou nd so far, the majority leading to classical INCL, Hum Mutat 15:273-279, 20 00, (C) 2000 Wiley-Liss, Inc.