Human RFT1 Deficiency Leads to a Disorder of N-Linked Glycosylation

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Human RFT1 Deficiency Leads to a Disorder of N-Linked Glycosylation Micha A. Haeuptle, François M. Pujol, Christine Neupert, Bryan Winchester, Alexander J. Kastaniotis, Markus Aebi, Thierry Hennet The American Journal of Human Genetics Volume 82, Issue 3, Pages 600-606 (March 2008) DOI: 10.1016/j.ajhg.2007.12.021 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Lipid-Linked and N-Linked Oligosaccharide Profiles The LLO isolated from healthy (A) and CDG (B) fibroblasts were separated by HPLC, demonstrating the abnormal accumulation of the LLO DolPP-GlcNAc2Man5 in the CDG sample. The NLO isolated from healthy (C) and CDG (D) fibroblasts were identical, showing that complete oligosaccharides were transferred to nascent proteins in the CDG cells. The retention times of DolPP-GlcNAc2Man1 (M1) to DolPP-GlcNAc2Man9Glc3 (M9G3) derived from a yeast standard LLO are marked at the top of the profiles. The American Journal of Human Genetics 2008 82, 600-606DOI: (10.1016/j.ajhg.2007.12.021) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 Mutation Analysis of Human RFT1 in CDG (A) Electropherograms of RFT1 cDNA surrounding nucleotide position 199, marked by an arrow, sequenced from healthy-control and patient cDNA. (B) The same region was sequenced from the genomic DNA of the CDG patient's parents, showing the heterozygozity for the c.199C→T mutation. (C) The resulting p.R67C substitution, marked with a star, was predicted to be localized in a hydrophilic loop within the highly hydrophobic RFT1 protein. A potential N-glycosylation site detected at position N227 is shown schematically. The American Journal of Human Genetics 2008 82, 600-606DOI: (10.1016/j.ajhg.2007.12.021) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 RFT1 Protein-Sequence Comparison Amino acid sequences of proteins derived from Homo sapiens, Mus musculus, Danio rerio, and Caenorhabditis elegans showing similarity to the Saccharomyces cerevisiae RFT1 protein as performed by ClustalW analysis.30 Residues conserved in all five species are shown in black. The R residue at position 67 in the human RFT1 protein (see arrow) is conserved in the five species. Total amino acid identity with the human sequence ranged from 87% for the mouse protein down to 22% for the S. cerevisiae Rft1 protein. The American Journal of Human Genetics 2008 82, 600-606DOI: (10.1016/j.ajhg.2007.12.021) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 4 Complementation of rft1Δ Yeasts (A) W1536 5B rft1Δ/pTSV30A-ScRFT1 cells transformed with a plasmid carrying a complementing RFT1 variant will form sectored colonies as they are allowed to lose the red pigment-inducing pTSV30A -ScRFT1 plasmid. Cells were transformed with: YCplac33 (mock), YCp33 GAL ScRFT1, YCp33 GAL hRFT1[R67C], and YCp33 GAL hRFT1. (B) Immunoblotting analysis of the yeast strain W1536 rftΔ transformed with yeast and human RFT1 expressed from the yeast GAL1 promoter showed near wild-type levels of carboxypeptidase Y glycosylation when grown on 2% Gal [G] and an accumulation of underglycosylated isoforms when RFT1 expression was repressed by 4% Glc [D]. Carbon source did not affect carboxypeptidase Y glycosylation in wild-type yeast. The American Journal of Human Genetics 2008 82, 600-606DOI: (10.1016/j.ajhg.2007.12.021) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 5 Lentiviral-Mediated Complementation in CDG Fibroblasts The LLO profiles of fibroblasts infected with recombinant lentiviruses expressing either human RFT1 (A) or EGFP as negative control (B) were analyzed. The profiles show that the expression of the normal RFT1 cDNA in CDG fibroblasts restored the synthesis of the complete LLO DolPP-GlcNAc2Man9Glc3. The expression of EGFP in CDG fibroblasts had no effect on the pathologic profile characterized by the accumulation of DolPP-GlcNAc2Man5. The retention times of DolPP-GlcNAc2Man1 (M1) to DolPP-GlcNAc2Man9Glc3 (M9G3) are marked at the top of the profiles. The American Journal of Human Genetics 2008 82, 600-606DOI: (10.1016/j.ajhg.2007.12.021) Copyright © 2008 The American Society of Human Genetics Terms and Conditions