Mutations in PGAP3 Impair GPI-Anchor Maturation, Causing a Subtype of Hyperphosphatasia with Mental Retardation Malcolm F. Howard, Yoshiko Murakami,

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Mutations in PGAP3 Impair GPI-Anchor Maturation, Causing a Subtype of Hyperphosphatasia with Mental Retardation Malcolm F. Howard, Yoshiko Murakami, Alistair T. Pagnamenta, Cornelia Daumer-Haas, Björn Fischer, Jochen Hecht, David A. Keays, Samantha J.L. Knight, Uwe Kölsch, Ulrike Krüger, Steffen Leiz, Yusuke Maeda, Daphne Mitchell, Stefan Mundlos, John A. Phillips, Peter N. Robinson, Usha Kini, Jenny C. Taylor, Denise Horn, Taroh Kinoshita, Peter M. Krawitz The American Journal of Human Genetics Volume 94, Issue 2, Pages 278-287 (February 2014) DOI: 10.1016/j.ajhg.2013.12.012 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees, Sanger Validation, and Phylogenetic Conservation of the Variant Filtering Cascade and Molecular Characterization of PGAP3 Mutations (A) Pedigrees are shown for family A (of Pakistani descent), family B (of European descent), and family C (of Saudi Arabian origin). Shading indicates ID and hyperphosphatasia, and proven heterozygote carriers are shown by a dot. In family A, the gray dotted lines indicate an additional consanguineous loop that was not described in the clinical notes but that was inferred by the high inbreeding coefficient detected in IV-2 from the SNP array data. The proband is indicated with an arrow. (B) Sanger validation and segregation testing of PGAP3 variants. DNA for the unaffected double first cousins in family A (collectively labeled as V-4) was not available. (C) ClustalW alignment of amino acid sequence shows high evolutionary conservation. The American Journal of Human Genetics 2014 94, 278-287DOI: (10.1016/j.ajhg.2013.12.012) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Photographs of Affected Individuals Facial features seen in (A) individual V-3 from family A, (B) individual II-1 from family B, and (C) individual II-1 from family C at the ages of 4, 10, and 2 years, respectively. These individuals bear a striking resemblance with a broad nasal bridge, long-appearing palpebral fissures, a broad nasal tip, a short nose, a long philtrum, a thin and wide upper lip, full cheeks, and large fleshy ear lobes. The American Journal of Human Genetics 2014 94, 278-287DOI: (10.1016/j.ajhg.2013.12.012) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 Flow Cytometric Analysis of Granulocyte Surface GPI-APs and Flow Cytometric Assay for Functions of Altered PGAP3 (A) Blood granulocytes from the affected individual in family B (solid line) were stained with anti-CD24 and anti-CD16 and fluorescence-labeled aerolysin (FLAER). The light-gray area represents a healthy control. (B) PGAP3 and PGAP2 double-mutant CHO cells were transfected with PGAP3 cDNA and 2 days later were stained for CD59, CD55 (DAF), and uPAR. (Bi) After transfection with wild-type PGAP3 cDNA, the surface levels of three GPI-APs were severely reduced (solid lines). The dark area shows the original surface levels of GPI-APs on PGAP3 and PGAP2 double-mutant CHO cells, whereas the light gray area represents the isotype-matched control. (Bii) The PGAP3 cDNA bearing mutation c.275G>A (p.Gly92Asp) in family A either did not reduce or only slightly reduced GPI-AP levels (solid lines). (Biii) The PGAP3 cDNA bearing one mutation, c.439dupC (p.Leu147Profs∗16), in family B did not reduce GPI-AP levels (solid lines), whereas that bearing the other mutation, c.914A>G (p.Asp305Gly), significantly reduced GPI-AP levels, indicating a hypomorphic mutant phenotype (dotted lines). (Biv) The PGAP3 cDNA bearing mutation c.314C>G (p.Pro105Arg) in family C slightly reduced the levels of three GPI-APs, indicating a hypomorphic but very severe loss-of-function phenotype (solid lines). The American Journal of Human Genetics 2014 94, 278-287DOI: (10.1016/j.ajhg.2013.12.012) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 4 SDS-PAGE and Immunoblotting of HA-Tagged PGAP3 (A) Lanes 1–3, wild-type; lanes 4–6, p.Asp305Gly; lanes 7–9, p.Gly92Asp. Protein levels shown as quantity were normalized with the intensities of GAPDH for the loading control and luciferase activities for the transfection efficiencies. The antibody showed no reactivity in lysates from empty-vector-transfected cells. (B) Lanes 1–3, wild-type; lanes 4–6, p.Pro105Arg. (C) Lane 1, wild-type; lane 2, p.Leu147Profs∗16; lane 3, empty vector. There are two N-glycosylation sites in PGAP3. The mature PGAP3 appears as a smear at 37–45 KDa (A, lane 3). This smear is sensitive to PNGase F, suggesting heterogeneous N-glycans. Bands seen below the 35 KDa position represent degradation products because they are not seen in the empty-vector transfectant (C, lane 3) or the transfectant with the truncated p.Leu147Profs∗16 protein (C, lane 2). Abbreviations are as follows: N, no treatment; P, PNGase F treatment; and E, Endo H treatment. The American Journal of Human Genetics 2014 94, 278-287DOI: (10.1016/j.ajhg.2013.12.012) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 5 Subcellular Localization of HA-Tagged PGAP3 in CHO Cells (First row) Wild-type. (Second row) p.Gly92Asp in family A. (Third row) p.Asp305Gly in family B. (Fourth row) Pro105Arg in family C. GM-130 is the Golgi marker. The relatively high levels of the ER form of HA-tagged wild-type PGAP3 seen in the top panels and also in lane 3 in Figure 4A might have been due to overexpression. The American Journal of Human Genetics 2014 94, 278-287DOI: (10.1016/j.ajhg.2013.12.012) Copyright © 2014 The American Society of Human Genetics Terms and Conditions