Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse.
Document Type
Article
Publication Date
2002
Keywords
Animal, Base-Sequence, Chromosome-Mapping, Chromosomes-Human-Pair-15, Costa-Rica, DNA-Mutational-Analysis, Exons, Female, Gene-Deletion, Gene-Frequency, Haplotypes, Human, Male, Membrane-Proteins, Mice, Molecular-Sequence-Data, Mutation, Neuronal-Ceroid-Lipofuscinosis, Pedigree, Polymorphism-(Genetics), RNA-Messenger, Sequence-Alignment, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, Venezuela
First Page
324
Last Page
335
JAX Source
Am J Hum Genet 2002 Feb; 70(2):324-35.
Grant
NS30170/NS/NINDS, NS33648/NS/NINDS
Abstract
The CLN6 gene that causes variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), a recessively inherited neurodegenerative disease that features blindness, seizures, and cognitive decline, maps to 15q21-23. We have used multiallele markers spanning this approximately 4-Mb candidate interval to reveal a core haplotype, shared in Costa Rican families with vLINCL but not in a Venezuelan kindred, that highlighted a region likely to contain the CLN6 defect. Systematic comparison of genes from the minimal region uncovered a novel candidate, FLJ20561, that exhibited DNA sequence changes specific to the different disease chromosomes: a G-->T transversion in exon 3, introducing a stop codon on the Costa Rican haplotype, and a codon deletion in exon 5, eliminating a conserved tyrosine residue on the Venezuelan chromosome. Furthermore, sequencing of the murine homologue in the nclf mouse, which manifests recessive NCL-like disease, disclosed a third lesion-an extra base pair in exon 4, producing a frameshift truncation on the nclf chromosome. Thus, the novel approximately 36-kD CLN6-gene product augments an intriguing set of unrelated membrane-spanning proteins, whose deficiency causes NCL in mouse and man.
Recommended Citation
Gao H,
Boustany RM,
Espinola JA,
Antonellis KA,
Gillis T,
Qin X,
Liu S,
Donahue LR,
Bronson RT,
et a.
Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet 2002 Feb; 70(2):324-35.