Ruth E Williams

The Gene Mutated in Variant Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN6) and in nclf Mutant Mice Encodes a Novel Predicted Transmembrane Protein

The neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative diseases characterized by the accumulation of autofluorescent lipopigment in various tissues and by progressive cell death in the brain and retina. The gene for variant late-infantile NCL (vLINCL), CLN6, was previously mapped to chromosome 15q21-23 and is predicted to be orthologous to the genes underlying NCL in nclf mice and in South Hampshire and Merino sheep. The gene underlying this disease has been identified with six different mutations found in affected patients and with a 1-bp insertion in the orthologous Cln6 gene in the nclf mouse. CLN6 encodes a novel 311-amino acid protein with seven predicted transmembrane domains, is conserved across vertebrates and has no homologies with proteins of known function. One vLINCL mutation, affecting a conserved amino acid residue within the predicted third hydrophilic loop of the protein, has been identified, suggesting that this domain may play an important functional role.

Refined genetic mapping of juvenile-onset neuronal ceroid-lipofuscinosis on chromosome 16

ConclusionWe propose that the most likely location for CLN3 is within the interval between loci D16S297 and D16S57 on the proximal portion of the short arm of chromosome 16. The position of the CLN3 gene could be further refined by the use of new polymorphic markers isolated within this interval.We have preliminary data indicating strong linkage disequilibrium with the disease for two markers, D16S298 and D16S299, and we find no recombination between these loci in the CEPH pedigrees (Thompson, Callen, Mitchison and Gardiner, unpublished). We therefore have a good indication that within our expected interval CLN3 is within close proximity of the locus D16S298/299.

Linkage analysis of late-infantile neuronal ceroid-lipofuscinosis (CLN2) using markers on chromosome 16p

ConclusionThese results provide further evidence of non-allelic genetic heterogeneity within the disorders grouped together as the neuronal ceroid-lipofuscinoses. There are at least three mutations at different loci involved in the pathogenesis of these disorders. The discrepancy in the extent of the regions excluded using data from the families with classical CLN2 and families with Finnish variant late-infantile NCL is due to the smaller number of families segregating for Finnish variant late-infantile NCL.