5 Positional cloning of the JNCL gene, CLN3

Abstract

Publisher Summary Juvenile neuronal ceroid lipofuscinosis (CLN3, JNCL, and Batten or Spielmeyer-Vogt-Sjogren disease, MIM304200) is the most common neurodegenerative disorder of childhood. Inheritance of the disease is autosomal recessive. There is no cure for JNCL. Treatment is largely symptomatic. Eiberg first mapped the JNCL locus CLN3 to chromosome 16. It is discovered a previously unreported subunit 9 gene, P3, and demonstrated the mapping of this gene to chromosome 2, also excluding it as the JNCL gene. Refined localization of CLN3 only became possible with the advent of highly polymorphic microsatellite markers. In parallel to efforts to refine the genetic locus of CLN3, a physical map consisting of yeast artificial chromosomes (YACs) and cosmid contigs is generated to span the candidate region. Cosmid clone NL11A, the most likely site of the JNCL gene CLN3, is selected for exon trapping for the isolation of candidate JNCL gene transcripts. The common mutation in JNCL is a 1-kb genomic deletion. The finding of additional mutations of the gene encoding cDNA2-3 in JNCL patients supported the conclusion that this gene is the JNCL gene CLN3. The tissue expression of CLN3 reflects the expression pattern of the other NCL genes so far identified, and offers no clue toward understanding the neuronal specificity of this group of disorders. No homology has been found at either the nucleotide or the protein level with any known gene, indicating that CLN3 encodes a novel protein of unknown function. The chapter discusses the animal models of JNCL. These animal models are critical for studies of the pathogenesis underlying the disease and for the evaluation of therapies.