Linkage disequilibrium between the juvenile neuronal ceroid lipofuscinosis gene and marker loci on chromosome 16p 12.1.
The neuronal ceroid lipofuscinoses (NCL; Batten disease) are a collection of autosomal recessive disorders characterized by the accumulation of autofluorescent lipopigments in the neurons and other cell types. Clinically, these disorders are characterized by progressive encephalopathy, loss of vision, and seizures. CLN3, the gene responsible for juvenile NCL, has been mapped to a 15-cM region flanked by the marker loci D16S148 and D16S150 on human chromosome 16. CLN2, the gene causing the late-infantile form of NCL (LNCL), is not yet mapped. We have used highly informative dinucleotide repeat markers mapping between D16S148 and D16S150 to refine the localization of CLN3 and to test for linkage to CLN2. We find significant linkage disequilibrium between CLN3 and the dinucleotide repeat marker loci D16S288 (chi 2(7) = 46.5, P < .005), D16S298 (chi 2(6) = 36.6, P < .005), and D16S299 (chi 2(7) = 73.8, P < .005), and also a novel RFLP marker at the D16S272 locus (chi 2(1) = 5.7, P = .02). These markers all map to 16p12.1. The D16S298/D16S299 haplotype "5/4" is highly overrepresented, accounting for 54% of CLN3 chromosomes as compared with 8% of control chromosomes (chi 2 = 117, df = 1, P < .001). Examination of the haplotypes suggests that the CLN3 locus can be narrowed to the region immediately surrounding these markers in 16p12.1. Analysis of D16S299 in our LNCL pedigrees supports our previous finding that CLN3 and CLN2 are different genetic loci. This study also indicates that dinucleotide repeat markers play a valuable role in disequilibrium studies.
Lerner
T J
TJ
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown 02129.
Boustany
R M
RM
MacCormack
K
K
Gleitsman
J
J
Schlumpf
K
K
Breakefield
X O
XO
Gusella
J F
JF
Haines
J L
JL
D002460:Cell Line; D002648:Child; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D008040:Genetic Linkage; D005819:Genetic Markers; D006801:Humans; D015810:Linkage Disequilibrium; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics*; D000091346:Tripeptidyl-Peptidase 1
D005819:Genetic Markers; D000091346:Tripeptidyl-Peptidase 1; C000717267:TPP1 protein, human