ABSTRACT
One variant form of late infantile neuronal ceroid lipofuscinosis (LINCL) is found predominantly within the Turkish population (CLN7). Exclusion mapping showed that CLN7 was not an allelic variant of known NCL loci (CLN1, CLN2, CLN3, CLN5 or CLN6). Using the method of homozygosity mapping, a genome-wide search was undertaken and a total of 358 microsatellite markers were typed at an average distance of about 10 cM. A region of shared homozygosity was identified on chromosome 8p23. This telomeric region contained the recently identified CLN8 gene. A missense mutation in CLN8 causes progressive epilepsy with mental retardation (EPMR) or Northern epilepsy, which has so far been reported only from Finland and is now classified as an NCL. The mouse model mnd has been shown to carry a 1 bp insertion in the orthologous Cln8 gene. Statistically significant evidence for linkage was obtained in this region, with LOD scores > 3, assuming either homogeneity or heterogeneity. Flanking recombinants defined a critical region of 14 cM between D8S504 and D8S1458 which encompasses CLN8. This suggests that Turkish variant LINCL, despite having an earlier onset and more severe phenotype, may be an allelic variant of Northern epilepsy. However mutation analysis has not so far identified a disease causing mutation within the coding or non-coding exons of CLN8 in the families. The Turkish variant LINCL disease-causing mutation remains to be delineated.
Subject(s)
Genetic Linkage , Neuronal Ceroid-Lipofuscinoses/genetics , Alleles , Child , Child, Preschool , Chromosome Mapping , DNA Mutational Analysis , DNA Primers , Family Health , Haplotypes , Homozygote , Humans , Infant , Microsatellite Repeats , Tripeptidyl-Peptidase 1 , TurkeyABSTRACT
To date two genes are known to be involved in variant LINCL, CLN5 and CLN6, which map to chromosomes 13q21 and 15q21-23. A subset of Turkish families with a variant phenotype has been identified. Affected individuals have curvilinear bodies and fingerprint profiles on EM but are recombinant at CLN5 and CLN6. These families appear to represent a new locus. Homozygosity mapping is being used to map this locus, which has been designated CLN7.
