Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse.
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.
Gao
Hanlin
H
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Boustany
Rose-Mary N
RM
Espinola
Janice A
JA
Cotman
Susan L
SL
Srinidhi
Lakshmi
L
Antonellis
Kristen Auger
KA
Gillis
Tammy
T
Qin
Xuebin
X
Liu
Shumei
S
Donahue
Leah R
LR
Bronson
Roderick T
RT
Faust
Jerry R
JR
Stout
Derek
D
Haines
Jonathan L
JL
Lerner
Terry J
TJ
MacDonald
Marcy E
ME
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003364:Costa Rica; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D016415:Sequence Alignment; D014687:Venezuela
C447500:CLN6 protein, human; C486722:Cln6 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger