Eija Siintola, Meral Topcu, Nina Aula, Hannes Lohi, Berge A

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The Novel Neuronal Ceroid Lipofuscinosis Gene MFSD8 Encodes a Putative Lysosomal Transporter Eija Siintola, Meral Topcu, Nina Aula, Hannes Lohi, Berge A. Minassian, Andrew D. Paterson, Xiao-Qing Liu, Callum Wilson, Ulla Lahtinen, Anna-Kaisa Anttonen, Anna-Elina Lehesjoki The American Journal of Human Genetics Volume 81, Issue 1, Pages 136-146 (July 2007) DOI: 10.1086/518902 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1. MFSD8-associated mutations. A, Sequence chromatograms showing homozygous MFSD8 mutations in six patients with vLINCL (f3, e3, j3, c3, h3, and b3) and the respective control (c) sequences. The mutated bases are underlined, and the vertical lines indicate exon-intron boundaries. B, Aberrant splicing of the c.754+2T→A mutant transcript. The agarose gel shows the mRNA splicing pattern in patient e5 (A/A), who is homozygous for c.754+2T→A, in his heterozygous carrier mother (T/A), and in a control individual (T/T), analyzed by RT-PCR with primers from exons 6 and 11. In the sample from patient e5, an altered pattern of PCR products is seen, with almost complete lack of the normal transcript (∼550 bp) containing exons 7–10, a complete lack of an alternatively spliced variant lacking exon 7 (Δ7) (∼400 bp), and increased expression of two alternatively spliced variants: one lacking exon 8 (Δ8) (∼500 bp) and one lacking exons 7 and 8 (Δ7+8) (∼350 bp). In addition, a faint band of ∼480 bp, the sequence of which remains unknown, is visible in the samples from patient e5 and his mother. The positions of the 100-bp ladder-size marker are shown on the left. The American Journal of Human Genetics 2007 81, 136-146DOI: (10.1086/518902) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2. Conservation of the MFSD8 amino acid sequence among human (Homo sapiens), mouse (Mus musculus), and zebrafish (Danio rerio). Amino acid sequences were aligned using MAFFT version 5.8. The amino acid numbering is indicated for the human polypeptide. Identical amino acids are indicated with gray shading. Sites of exonic disease-causing mutations are marked with an asterisk (*): p.Arg233Gly/splice, p.Tyr298X, p.Gly310Asp, p.Asp368His/splice, and p.Gly429Asp. The predicted 12 transmembrane domains are indicated with boxes and Roman numerals. The American Journal of Human Genetics 2007 81, 136-146DOI: (10.1086/518902) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3. Northern-blot analysis of MFSD8 expression. An ∼5-kb MFSD8 transcript (upper panels) was detected in all tissues analyzed. In all brain regions and in lung, it is the only transcript seen. In other tissues, transcripts that ranged in size from ∼1 to ∼3 kb and/or ∼6 kb were also present. Lower panels, Hybridization with human β-actin cDNA as a control for RNA loading. The positions of size markers are shown on the left of each blot. The American Journal of Human Genetics 2007 81, 136-146DOI: (10.1086/518902) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4. Schematic structure of the MFSD8 protein, with positions of patient mutations that affect exonic sequences. MFSD8 is predicted to contain 12 transmembrane domains, according to the prediction programs HMMTOP, TMHMM, and TMpred. The site of the nonsense mutation (p.Tyr298X) is indicated with a square, the site of the missense mutations (p.Gly310Asp and p.Gly429Asp) with circles, and the site of mutations that either change amino acids or affect splicing (p.Arg233Gly/splice and p.Asp368His/splice) with crosses. The American Journal of Human Genetics 2007 81, 136-146DOI: (10.1086/518902) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 5. Lysosomal localization of both wild-type and mutant MFSD8 proteins. Subcellular localization of HA-tagged wild-type (wt) and mutant (G310D and G429D) MFSD8 was seen in transiently transfected COS-1 cells. A, D, and G, Distribution of the HA-MFSD8 protein by use of an antibody against HA (red). B, Lysosomal staining pattern by use of an anti–Lamp-1 antibody (green). C, Overlay of the HA-MFSD8 and Lamp-1 stainings. E, Early endosomal staining pattern by use of an anti-EEA1 antibody (green). F, Overlay of the HA-MFSD8 and EEA1 stainings. H, Trans-Golgi-network staining pattern by use of an anti-MPR46 antibody (green). I, Overlay of the HA-MFSD8 and MPR46 stainings. J and M, Distribution of the G310D mutant (J) and the G429D mutant (M) HA-MFSD8 proteins by use of an antibody against HA (red). K and N, Lysosomal staining pattern by use of an anti–Lamp-1 antibody (green). L and O, Overlays of the mutant HA-MFSD8 and Lamp-1 stainings. Yellow indicates overlap of wild-type or mutant HA-MFSD8 and the subcellular markers. Scale bars (10 μm) are shown in panels C, F, I, L, and O. The American Journal of Human Genetics 2007 81, 136-146DOI: (10.1086/518902) Copyright © 2007 The American Society of Human Genetics Terms and Conditions