CLN5, A NOVEL GENE ENCODING A PUTATIVE TRANSMEMBRANE PROTEIN MUTATED IN FINNISH VARIANT LATE INFANTILE NEURONAL CEROID-LIPOFUSCINOSIS

The neuronal ceroid lipofuscinoses (NCLs) represent a group of common recessive inherited neurodegenerative disorders of childhood, with an incidence of 1:12,500 live births(1). They are characterized by accumu lation of autofluorescent lipopigments in various tissues. Several for ms of NCLs have been identified, based on age at onset, progression of disease, neurophysiological and histopathological findings and separa te genetic loci(2-9) All types of NCL cause progressive visual and men tal decline, motor disturbance, epilepsy and behavioral changes, and l ead to premature death. One of the subtypes, Finnish variant late infa ntile neuronal ceroid lipofuscinosis (vLINCL; MIM256731) affects child ren at 4-7 years of age(10,11). The first symptom is motor clumsiness, followed by progressive visual failure, mental and motor deterioratio n and later by myoclonia and seizures. We have previously reported lin kage for vLINCL on chromosome 13 (ref. 5) and constructed a long-range physical map over the region(12). Here, we report the positional clon ing of a novel gene, CLN5, underlying this severe neurological disorde r. The gene encodes a putative transmembrane protein which shows no ho mology to previously reported proteins. Sequence analysis of DNA sampl es from patients with three different haplotypes revealed three mutati ons; one deletion, one nonsense and one missense mutation, suggesting that mutations in this gene are responsible for vLINCL.