Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia Thi Tuyet Mai.

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Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia Thi Tuyet Mai Nguyen, Yoshiko Murakami, Eamonn Sheridan, Sophie Ehresmann, Justine Rousseau, Anik St-Denis, Guoliang Chai, Norbert F. Ajeawung, Laura Fairbrother, Tyler Reimschisel, Alexandra Bateman, Elizabeth Berry-Kravis, Fan Xia, Jessica Tardif, David A. Parry, Clare V. Logan, Christine Diggle, Christopher P. Bennett, Louise Hattingh, Jill A. Rosenfeld, Michael Scott Perry, Michael J. Parker, Françoise Le Deist, Maha S. Zaki, Erika Ignatius, Pirjo Isohanni, Tuula Lönnqvist, Christopher J. Carroll, Colin A. Johnson, Joseph G. Gleeson, Taroh Kinoshita, Philippe M. Campeau The American Journal of Human Genetics Volume 101, Issue 5, Pages 856-865 (November 2017) DOI: 10.1016/j.ajhg.2017.09.020 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees and Clinical Images (A) Pedigrees of the five families affected by GPAA1 mutations in this study. (B) MRI of individual 4b (VII-2 of family 4) at 25 months. T1 sagittal image shows a marked reduction in cerebellar volume. (C) Starting from the top right, photographs of individuals 1a (age 15 years), 1b (age 10 years), 3a (age 10 years), 3b (age 3 years), and 5 (age 25 years). A slightly broad and prominent root of the nose is noted in individuals 1b, 3b, and 5. The American Journal of Human Genetics 2017 101, 856-865DOI: (10.1016/j.ajhg.2017.09.020) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Mutation Localization and Residue Conservation (A) Location of the protein variants in GPAA1 (for the splicing variant, the site affected by the exon-exon junction is shown). (B) Amino acid conservation in vertebrates of the amino acids affected by substitution mutations. The American Journal of Human Genetics 2017 101, 856-865DOI: (10.1016/j.ajhg.2017.09.020) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 GPAA1 Expression by qRT-PCR in Individuals from Families 1 and 2 (A and B) RNA extractions from fibroblasts (A) and LCLs (B) of individuals 1a, 1b, and 2 were subjected to qRT-PCR. Graphs show the results normalized to a reference gene (TBP for fibroblasts and GAPDH for LCLs) from quadruplicate experiments. Error bars represent standard deviations from the mean. (C) GPI-AP abundance in granulocytes of individuals from families 1, 2, and 4. Fresh blood samples from these individuals and samples from healthy control individuals were fixed with 10% formaldehyde; red blood cells were lysed in 0.1% Triton X-100, and the samples were stained with GPI-AP markers (FLAER and CD16) for 1 hr at room temperature. Non-specific binding was washed before analysis by the BD FACScanto II system. Shown are representative results from experiments done in triplicate. (D) GPI-AP abundance in LCLs of individuals from families 1, 2 and 4. LCLs were established by Epstein-Barr virus immortalization of peripheral-blood mononuclear cells. Cells were stained with a GPI-AP marker (FLAER) for 1 hr at room temperature. Non-specific binding was washed before analysis of the cell-surface abundance of GPI-APs by the BD FACScanto II system. Shown are representative results from experiments done in triplicate. The American Journal of Human Genetics 2017 101, 856-865DOI: (10.1016/j.ajhg.2017.09.020) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 4 Activity in GPAA1-Knockout Cells (A) Rescue of GPAA1-knockout cells. GPAA1-knockout cells were transiently transfected with a plasmid encoding wild-type or variant GPAA1 under the control of a weak promoter (pTA plasmid) by lipofection. Transfection efficiency was monitored by luciferase assay, and flow-cytometry analysis was performed 2 days after transfection. These results show slightly decreased labeling only for the p.Ser51Leu and p.Ala389Pro variants (fewer cells with a strong signal), possibly because the residual activity of the other variants was sufficient to provide a rescue in this experiment. (B) The p.Ala389Pro variant leads to protein instability. HEK293 cells were transiently transfected with various GPAA1 cDNAs, and proteins were analyzed by western blotting with an anti-FLAG antibody (Sigma). Intensities of the bands were normalized with the loading control (GAPDH), and luciferase activity was used for evaluating transfection efficiencies. The western blot of the tagged protein indicates that p.Ala389Pro, in the second transmembrane domain, leads to protein instability. The American Journal of Human Genetics 2017 101, 856-865DOI: (10.1016/j.ajhg.2017.09.020) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 5 Lentiviral Rescue Assays in Fibroblasts from Individuals 1a and 2 Skin fibroblasts derived from individuals 1a and 2 were transduced with GPAA1-expressing Lv105 lentivirus or empty-vector lentivirus and then transduced, and non-transduced cells were stained with CD109 and CD73 for 1 hr at room temperature. The non-specific binding was washed before analysis of the cell-surface abundance of GPI-APs by the BD FACScanto II system. Shown are representative results from experiments done in triplicate. The American Journal of Human Genetics 2017 101, 856-865DOI: (10.1016/j.ajhg.2017.09.020) Copyright © 2017 American Society of Human Genetics Terms and Conditions