Progress toward the cloning of CLN6, the gene underlying a variant LINCL.

Marked clinical heterogeneity is seen in the late-infantile subtype of NCL (LINCL), complicating genetic analysis. In addition to the classical subtype, encoded by CLN2 on chromosome 11p15.5, several variant subtypes have also been described. In this paper, we report our progress in cloning a variant LINCL gene mapped in a small group of Costa Rican families. Clinically, these patients appear similar to classical LINCL patients, except onset of the disease is delayed and the course is milder. Extended haplotype analysis confirms the localization of this gene to chromosome 15q21-22, where CLN6 has also been mapped. Using now-standard positional cloning techniques, we have developed a physical map of our candidate region. These clones have been used to order genetic markers, STSs, and ESTs in this region and will be used for the identification of the disease gene transcript.

Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis.

Classical late-infantile neuronal ceroid lipofuscinosis (LINCL; CLN2) is an inherited neurodegenerative disorder of childhood characterized by seizures, loss of vision, and progressive motor and mental deterioration. The hallmark of this disease is the accumulation of enlarged, secondary lysosomes packed with curvilinear bodies in cells of affected individuals. The biochemical basis of LINCL remains unknown and there is no treatment effective in delaying the progression of this fatal disorder. During a genome-wide search using a set of highly polymorphic markers and 15 affected individuals from 7 multi-affected families, we obtained evidence for linkage of the LINCL gene CLN2 with markers on chromosome 11p15.5. We then genotyped patients and all available family members, including 8 single-affected families, for markers spanning 15 cM of 11p15.5. We obtained a maximum two-point LOD score of 6.16 at 0 = 0.00 at the marker locus D11S2362. Multipoint analysis yielded a maximum LOD score of 6.90 localized to the same marker. Using haplotype analysis, we localized CLN2 to a minimum candidate region of 11 cM flanked by marker loci D11S4046 on the telomeric side and D11S1996 on the centromeric side. Additionally, we present data suggesting that the gene underlying a variant LINCL subtype found in Costa Rica maps to the region defined by the CLN6 locus on chromosome 15q21-23. The mapping of these two LINCL loci provides a genetic basis for understanding the clinical heterogeneity observed in this group of diseases.