The Phenotype of a Germline Mutation in PIGA: The Gene Somatically Mutated in Paroxysmal Nocturnal Hemoglobinuria Jennifer J. Johnston, Andrea L. Gropman,

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The Phenotype of a Germline Mutation in PIGA: The Gene Somatically Mutated in Paroxysmal Nocturnal Hemoglobinuria Jennifer J. Johnston, Andrea L. Gropman, Julie C. Sapp, Jamie K. Teer, Jodie M. Martin, Cyndi F. Liu, Xuan Yuan, Zhaohui Ye, Linzhao Cheng, Robert A. Brodsky, Leslie G. Biesecker The American Journal of Human Genetics Volume 90, Issue 2, Pages 295-300 (February 2012) DOI: 10.1016/j.ajhg.2011.11.031 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Phenotype of IV-2 and IV-4 (A–C) Individual IV-2. (A) Craniofacial features including micrognathia, a prominent occiput, a depressed nasal bridge, a short, anteverted nose, malar flattening, upslanted palpebral fissures, a small, triangular mouth, downturned corners of the mouth, and a short neck. (B) Sagittal T1-weighted cranial MRI demonstrates thinning of the genu of the corpus callosum, mild sulcal prominence, and cerebellar hypoplasia. (C) Axial T1-weighted MRI demonstrates white-matter or myelination immaturity for the individual's age. (D–F) Individual IV-4. (D) Facial image showing similar facial features to those of IV-2. (E) Sagittal T1 cranial MRI demonstrates a thin corpus callosum, sulcal prominence, and a small cerebellum. (F) Axial T1-weighted cranial MRI demonstrates white-matter immaturity. The American Journal of Human Genetics 2012 90, 295-300DOI: (10.1016/j.ajhg.2011.11.031) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Identification and Segregation of the PIGA Mutation (A) Pedigree showing segregation of carrier or affected status with the presence of the mutation (+, wild-type; M, mutant). (B) Filtering criteria used for identification of the mutation from a total of 1,360 variants identified in individual III-2. (C) Sanger sequence verification; an arrow shows the position of the mutation. The American Journal of Human Genetics 2012 90, 295-300DOI: (10.1016/j.ajhg.2011.11.031) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Reduced Activity of the p.Arg412∗ PIGA Mutant in Restoring Surface Expression of GPI-Anchored Protein after Transfection into PIGA-Null Cell Lines Flow-cytometry analysis showing that cell-surface expression of CD59, a GPI-anchored protein, is absent in both LD cells (A, left panel) and TF1-PNH cells (A, right panel). Seventy-two hours after transfection, the cells that received vector expressing wild-type PIGA (pPB-wtPIGA) significantly upregulated surface CD59 expression (C) in comparison to those that received empty vector controls (B). The expression of mutant PIGA (pPB-mutPIGA) partially restored the surface expression of CD59 (D). The American Journal of Human Genetics 2012 90, 295-300DOI: (10.1016/j.ajhg.2011.11.031) Copyright © 2012 The American Society of Human Genetics Terms and Conditions