PGAP2 Mutations, Affecting the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation Syndrome Peter M. Krawitz, Yoshiko Murakami,

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PGAP2 Mutations, Affecting the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation Syndrome Peter M. Krawitz, Yoshiko Murakami, Angelika Rieß, Marja Hietala, Ulrike Krüger, Na Zhu, Taroh Kinoshita, Stefan Mundlos, Jochen Hecht, Peter N. Robinson, Denise Horn The American Journal of Human Genetics Volume 92, Issue 4, Pages 584-589 (April 2013) DOI: 10.1016/j.ajhg.2013.03.011 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Phenotypic Features of HPMRS Associated with Mutations in PGAP2 (A and B) Face of individual A from family A at the ages of 3 (A) and 28 years (B). (C) Normal-appearing fingernails of the affected individual in family A. (D and E) Facial dysmorphism of the affected individual in family B at the age of 2 years includes wide palpebral fissures, a short nose with a broad nasal bridge, a tented upper lip, and a small jaw. (F) Distal tapering of fingers and mild nail hypoplasia of the fifth digit of the affected individual in family B. The American Journal of Human Genetics 2013 92, 584-589DOI: (10.1016/j.ajhg.2013.03.011) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 Identification and Segregation of the PGAP2 Mutations Pedigrees showing segregation of the HPMRS phenotype with deleterious variants in PGAP2 in families A (A) and B (B). Circles represent females, squares represent males, filled symbols represent affected individuals, and dots within the symbols represent heterozygotes. Sequence reads show the mutation in short read alignments visualized in integrative genome viewer. The American Journal of Human Genetics 2013 92, 584-589DOI: (10.1016/j.ajhg.2013.03.011) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 3 Reduced Activity of Altered Forms of PGAP2 in Restoring Surface Expression of GPI-Anchored Proteins after Transfection into PGAP2-Null Cell Lines PGAP2-deficient CHO cells were transiently transfected with wild-type or altered forms (p.Arg16Trp, p.Thr160Ile [family A], and p.Leu127Ser [family B]) of pTA Flag-PGAP2 isoform 8 driven by a weak promoter. Restoration of the surface expression was assessed 2 days later by flow cytometry. p.Arg16Trp and p.Thr160Ile detected in family A and p.Leu127Ser detected in family B did not restore the surface expression of CD59 and CD55 as efficiently as the wild-type PGAP2. The reduction of surface protein levels associated with p.Arg16Trp was less severe. This correlates with a lower sequence conservation of this position and a milder phenotype in individual II-1of family A. The American Journal of Human Genetics 2013 92, 584-589DOI: (10.1016/j.ajhg.2013.03.011) Copyright © 2013 The American Society of Human Genetics Terms and Conditions