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: 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
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 70 Issue 2 Pg. 324-35 (Feb 2002) ISSN: 0002-9297 [Print] United States
• PMID: 11791207 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CLN6 protein, human
• Cln6 protein, mouse
• Membrane Proteins
• RNA, Messenger

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• Chromosome Mapping
• Chromosomes, Human, Pair 15 (genetics)
• Costa Rica
• DNA Mutational Analysis
• Exons (genetics)
• Female
• Gene Deletion
• Gene Frequency (genetics)
• Haplotypes (genetics)
• Humans
• Male
• Membrane Proteins (chemistry, deficiency, genetics)
• Mice
• Molecular Sequence Data
• Mutation (genetics)
• Neuronal Ceroid-Lipofuscinoses (genetics)
• Pedigree
• Polymorphism, Genetic (genetics)
• RNA, Messenger (analysis, genetics)
• Sequence Alignment
• Venezuela