2 COMMON MUTATIONS IN THE CLN2 GENE UNDERLIE LATE INFANTILE NEURONAL CEROID-LIPOFUSCINOSIS

Late infantile neuronal ceroid lipofuscinosis (LINCL) is one of the mo st common pediatric neuronal degenerative disorders. A candidate gene underlying this disease, designated CLN2, was recently cloned and the gene product was characterized as a lysosomal pepstatin-insensitive ca rboxypeptidase (LPIC). Four mutations were identified in CLN2 from thr ee unrelated LINCL individuals. To investigate further the mutation fr equency in LINCL, we screened 16 LINCL probands for these four mutatio ns. The previously reported intronic mutation, T523-1 G --> C, was fou nd in 56% (9/16) of the cases, of which two were homozygous and accoun ted for 34% (11/32) of LINCL chromosomes. The previously reported nons ense mutation, 636 C --> T leading to R208stop, was found in 31% (5/16 ) of the cases, including one homozygote and accounted for 19% (6/32) of LINCL chromosomes. Two previously described missense mutations, 110 7 T --> C and 1108 G --> A, were not detected in any of these 16 proba nds. In total, the two observed mutations, T523-1 G --> C and 636 C -- > T, accounted for 53% (17/32) of LINCL alleles. Thus, one or both mut ations were seen in 11 (69%) cases and no mutation has yet been identi fied in five. Our finding that these two mutations are common in LINCL cases adds further evidence in support of the idea that dysfunction o f LPIC underlies LINCL. Positive molecular testing can now complement clinical diagnosis of LPIC and will allow for pre-natal diagnosis for subsequent pregnancies.