The Gene Mutated in Variant Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN6) and in nclf Mutant Mice Encodes a Novel Predicted Transmembrane Protein

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The Gene Mutated in Variant Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN6) and in nclf Mutant Mice Encodes a Novel Predicted Transmembrane Protein Ruth B. Wheeler, Julie D. Sharp, Roger A. Schultz, John M. Joslin, Ruth E. Williams, Sara E. Mole The American Journal of Human Genetics Volume 70, Issue 2, Pages 537-542 (February 2002) DOI: 10.1086/338708 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Electropherograms showing genomic nucleotide sequence across mutation sites in two patients and the nclf mouse. a, Homozygous 1-bp insertion in exon 4 in a Pakistani patient (c.316insC). b, Normal control sequence. c, A 3-bp deletion in exon 4 in a Portuguese patient (c.460_462delATC). d, Normal control sequence. e, A homozygous 1-bp insertion in exon 4 in the nclf mouse (c.301insC). f, Wild-type sequence. The nclf mouse DNA was obtained from The Jackson Laboratory (stock no. 002628). Mutations were detected by direct sequencing of genomic PCR products. PCR and sequencing primers are listed in the supplementary information. Each primer pair amplified the corresponding exon and the flanking splice sites. PCR products were sequenced using ABI dye terminator chemistry (Applied Biosystems) and were visualized on an ABI 373 sequencer (Applied Biosystems). Mutations were confirmed by sequencing in both directions. The American Journal of Human Genetics 2002 70, 537-542DOI: (10.1086/338708) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 A, Schematic representation of CLN6 structure, showing the seven predicted transmembrane domains based on TMHMM and TMAP programs and hydrophobicity profiles. Single–amino-acid changes are indicated by asterisks (*). Exoplasmic and cytoplasmic surfaces are indicated. B, Kyte and Doolittle hydrophobicity plot of the predicted CLN6 protein. All prediction programs were run using the Biology Workbench. The American Journal of Human Genetics 2002 70, 537-542DOI: (10.1086/338708) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 A comparison between human and mouse CLN6 amino acid sequences. Dark shading indicates identical amino acids, and gray shading indicates similar amino acids. Asterisks (*) denote the amino acid removed by the 3-bp deletion in a Portuguese patient (I154del) and the missense mutation in the Costa Rican patient (G123D). Human and mouse protein sequences were aligned using ClustalW (Thompson et al. 1997) and MacBoxshade 2.15E. The American Journal of Human Genetics 2002 70, 537-542DOI: (10.1086/338708) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 4 Human multiple-tissue northern blot (Clontech) probed with a [32P]-labeled 808-bp fragment of CLN6 cDNA spanning from exon 3 to the 3′ UTR, according to the manufacturer's instructions. In all tissues, 2.4-kb and 3.7-kb transcripts were detected, with additional transcripts of 1.1 kb and 5.9 kb detected only in skeletal muscle. A β-actin probe was used as a control for lane loading. The American Journal of Human Genetics 2002 70, 537-542DOI: (10.1086/338708) Copyright © 2002 The American Society of Human Genetics Terms and Conditions