Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse

Hanlin Gao, Rose Mary N. Boustany, Janice A. Espinola, Susan L. Cotman, Lakshmi Srinidhi, Kristen Auger Antonellis, Tammy Gillis, Xuebin Qin, Shumei Liu, Leah R. Donahue, Roderick T. Bronson, Jerry R. Faust, Derek Stout, Jonathan L. Haines, Terry J. Lerner, Marcy E. MacDonald

Research output: Contribution to journalArticlepeer-review

176 Scopus citations

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 μ4-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, ancl a codon deletion in exon 5, eliminating a conserved tyrosine resiclue 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 μ36-kD CLN6-gene product augments an intriguing set of unrelated membrane-spanning proteins, whose deficiency causes NCL in mouse and man.

Original languageEnglish
Pages (from-to)324-335
Number of pages12
JournalAmerican Journal of Human Genetics
Volume70
Issue number2
DOIs
StatePublished - 2002
Externally publishedYes

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