Elsevier

Genomics

Volume 50, Issue 2, 1 June 1998, Pages 206-212
Genomics

Regular Article
Structural Organization and Sequence ofCLN2,the Defective Gene in Classical Late Infantile Neuronal Ceroid Lipofuscinosis,☆☆

https://doi.org/10.1006/geno.1998.5328Get rights and content

Abstract

Mutations in the CLN2 gene result in classical late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal childhood neurodegenerative disease. In this report, we present the complete sequence of the human CLN2 gene and define its physical relationship with two other genes that have been previously mapped to chromosome 11p15. The CLN2 gene consists of 13 exons and 12 introns and spans 6.65 kb. By S1 mapping and primer extension, the 5′-terminus of the CLN2 mRNA was mapped to 32 nucleotides upstream of the proposed initiation codon. A number of other elements were found to be located in close proximity to CLN2, including the gene encoding transcription factor TAFII30, the gene encoding intregrin-linked kinase, and an ∼914-bp fragment that is 82% identical to antithrombin III. In addition, an EST cDNA clone that is transcribed on the strand opposite to CLN2 and that overlaps a portion of the CLN2 gene was identified. Finally, a set of primer pairs are presented for the amplification of the coding sequences, putative promoter, and splice junctions of the CLN2 gene. Taken together, this information will facilitate the molecular analysis of and genetic testing for classical LINCL.

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    The clinical disease is manifested by progressive retinal degeneration and vision loss as well as widespread neurodegeneration accompanied by progressive brain atrophy, severe decline in cognitive and motor functions, seizures, and premature death (Mole et al., 2011). The CLN2 form of NCL is caused by mutations in the TPP1 gene that result in deficiencies in functional tripeptidyl peptidase-1 (TPP1) (Liu et al., 1998; Mole and Cotman, 2015; Sleat et al., 1997). TPP1 is a soluble lysosomal enzyme involved in the normal degradation of proteins and peptides in cells throughout the body.

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    The Cln2 gene (Ceroid lipofuscinosis, neuronal, 2) (MIM #607998) is a 6.65 kb gene comprised of 13 exons and 12 introns mapped to chromosome 11p15.5. ( Liu et al., 1998; Haines et al., 1998) and encodes a 563-amino acid containing TPP1 preproenzyme which following removal of signal peptide, glycosylation and cleavage yields the 367 residue long 46 kD mature active TPP1 enzyme (Golabek et al., 2003; Sondhi et al., 2001). The protein TPP1 progressively eliminates tripeptides from the N-terminus of small polypeptides, one of which is the subunit c of mitochondrial ATP synthase (SCMAS), the major constituent of the storage granules in LINCL (Crystal et al., 2004; Sohar et al., 1999).

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Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under Accession No. AF039704.

☆☆

V. B. Chanda

1

These authors contributed equally to the work contained within this article.

2

To whom correspondence should be addressed. Telephone: (732) 235-5360. Fax: (732) 235-4850. E-mail:[email protected].

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