MOLECULAR BASIS OF LATE INFANTILE NCL

描述：（来自摘要）本研究的长期目标

DESCRIPTION: (From Abstract) The long-term objective of this research is to understand the molecular basis of neuronal ceroid lipofuscinosis (NCL; Batten disease). NCL is the most common neurodegenerative disorder of childhood and is characterized by progressive mental deterioration, seizures, and vision loss. The hallmark of the disease is the accumulation of autofluorescent lipopigments in ultrastructural cytosomes in neurons and other cell types. Five major sub-types are now recognized on the basis of age-at-onset, clinical presentation, and ultrastructural morphology: infantile (INCL), found exclusively in the Finnish population; late infantile (LNCL); juvenile (JNCL); and adult (Kufs disease). With the possible exception of the adult form, inheritance is autosomal recessive. The incidence of NCL is estimated at 1-5/100,000. Despite intensive effort, the basic biochemical defect in NCL continues to elude researchers. There is no effective treatment for this fatal disease. The loci for the juvenile (CLN3), infantile (CLN1) types, and CLN5 have been mapped by genetic linkage analysis to chromosome 16p, 1p, and 13q respectively. The late infantile defect (CLN2) has not yet been mapped, although linkage analysis with tightly linked markers excludes it from the JNCL locus on chromosome 16 and the INCL locus on chromosome 1. The first goal of this current proposal is to use genetic linkage methods with highly polymorphic markers to localize and refine the map position of the CLN2. This information will be used to implement a positional cloning strategy for the isolation and subsequent characterization of the gene. Throughout this project period, candidate genes will be evaluated for their role in the pathogenesis of NCL by biochemical and histological studies and by our analysis of candidate JNCL genes. With the identification of closely-linked highly informative flanking markers, DNA-based pre-natal and pre-symptomatic diagnosis can be offered to at-risk families well before the actual cloning and characterization of the disease gene. The identification of mutations within the gene will allow carrier testing in selected populations. Knowledge of the molecular defect underlying LNCL will help elucidate the biochemical pathways involved in the pathogenesis of the disease, shed light on the possible cause of the other ceroid lipofuscinoses, and provide a starting point for the design of rational therapies.