title: Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse.
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.
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Hanlin
authors.initials: H
authors.lastname: Gao
authors.forename: Rose-Mary N
authors.initials: RM
authors.lastname: Boustany
authors.forename: Janice A
authors.initials: JA
authors.lastname: Espinola
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cotman
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Srinidhi
authors.forename: Kristen Auger
authors.initials: KA
authors.lastname: Antonellis
authors.forename: Tammy
authors.initials: T
authors.lastname: Gillis
authors.forename: Xuebin
authors.initials: X
authors.lastname: Qin
authors.forename: Shumei
authors.initials: S
authors.lastname: Liu
authors.forename: Leah R
authors.initials: LR
authors.lastname: Donahue
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Faust
authors.forename: Derek
authors.initials: D
authors.lastname: Stout
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Lerner
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
mesh_terms: 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
chemical_list: C447500:CLN6 protein, human; C486722:Cln6 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger