Mutations in PIGO, a Member of the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation Peter M. Krawitz, Yoshiko Murakami,

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Mutations in PIGO, a Member of the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation Peter M. Krawitz, Yoshiko Murakami, Jochen Hecht, Ulrike Krüger, Susan E. Holder, Geert R. Mortier, Barbara Delle Chiaie, Elfride De Baere, Miles D. Thompson, Tony Roscioli, Szymon Kielbasa, Taroh Kinoshita, Stefan Mundlos, Peter N. Robinson, Denise Horn The American Journal of Human Genetics Volume 91, Issue 1, Pages 146-151 (July 2012) DOI: 10.1016/j.ajhg.2012.05.004 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Schematic Illustration of Biochemical Reactions of Late GPI-Anchor Synthesis The first, second, and third mannose residues are sequentially transferred to GlcN-(acyl)PI by PIGM, PIGV, and PIGB. EtNP is transferred to the first mannose by PIGN and to the third mannose by PIGO and PIGF. Proteins for which the corresponding mutated genes are known to cause congenital disorders of GPI-anchor glycosylation are colored black. The American Journal of Human Genetics 2012 91, 146-151DOI: (10.1016/j.ajhg.2012.05.004) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Affected Individuals from Family A (A) Facial appearance of individual II-1 at the age of 15 years. (B) Individual II-2 at the age of 12 years. (C) Nail hypoplasia of the second and fourth digits and absent nail of the fifth digit in individual II-1. (D) Broad hallux, small nails of the second and third toes, and aplasia of the nails of the fourth and fifth digits in individual II-1. The American Journal of Human Genetics 2012 91, 146-151DOI: (10.1016/j.ajhg.2012.05.004) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Individual II-1 from Family B at Different Ages (A) When individual II-1 was 6 weeks of age, facial dysmorphism included wide and downward-slanting palpebral fissures, a broad nasal bridge and tip, ptosis of the right eye, a tented upper lip, large ears with fleshy and uplifted ear lobules, and facial asymmetry. (B) Facial appearance when individual II-1 was 9 months old. (C) At the age of 18 months. (D) Nail hypoplasia of the second and fifth digits and clinodactyly V. (E) Hand radiograph when individual II-1 was 1 week old. Note brachytelephalangy II to V, mostly affecting fingers II and V, and a broad distal phalanx of the thumb. (F) Nail hypoplasia of all toes. The American Journal of Human Genetics 2012 91, 146-151DOI: (10.1016/j.ajhg.2012.05.004) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Mutations in PIGO (A) PIGO mutations in family A as demonstrated by whole-exome sequencing. Both affected daughters were found to be compound heterozygous for the PIGO mutations c.2869C>T and c.2361dup. The father is heterozygous for c.2361dup, and the mother is heterozygous for c.2869C>T. (B) The affected individual from family B is compound heterozygous for c.2869C>T and c.3069+5G>A. Her mother and healthy brother II-3 are heterozygous only for c.3069+5G>A, and her healthy brother II-2 is heterozygous only for c.2869C>T. (C) The intronic mutation results in an aberrant splicing product of transcript NM_032634, which is missing 215-bp-long exon 9. The American Journal of Human Genetics 2012 91, 146-151DOI: (10.1016/j.ajhg.2012.05.004) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 5 PIGO Activity Is Required for Linking GPI-Anchored Substrates to the Cell Membrane (A) PIGO-deficient CHO cells were transiently transfected with human wild-type (dotted lines), p.Thr788Hisfs∗5 (dashed line), or p.L957F (solid lines) PIGO cDNA expression constructs. Restoration of the levels of CD59 at the cell surface and of uPAR was assessed 2 days later. Wild-type PIGO efficiently restored levels of CD59 at the cell surface and of uPAR, whereas Thr788Hisfs∗5 PIGO did not restore the level of CD59 at all and the Leu957Phe PIGO induced only very low levels of CD59 and uPAR. The shadowed area indicates an empty-vector transfectant (control). (B) PIGO levels. The level of the truncated Thr788Hisfs∗5 PIGO (lane 3) was about 2.5× higher than that of wild-type PIGO (lane 2), and the level of Leu957Phe PIGO (lane 4) was slightly lower than that of wild-type PIGO (lane 2). (C) The level of PLAP at the cell surface after cotransfection with PIGO into PIGO-deficient CHO cells. PIGO-deficient CHO cells were transiently transfected with pME HA-PLAP together with pME PIGO (dotted line) or an empty vector (solid line). The level of PLAP at the cell surface was analyzed by fluorescence-activated cell sorting. PLAP activity was measured in culture medium and cell lysates after cotransfection of PLAP and PIGO cDNAs into PIGO-deficient CHO cells. Relative ALP activity was measured in culture medium (black bars) and in cell lysates (dark gray bar) against the total ALP activity in PIGO-restored CHO cells. Restoration of PIGO activity reduces ALP activity in the medium and increases activity at the cell membrane. The American Journal of Human Genetics 2012 91, 146-151DOI: (10.1016/j.ajhg.2012.05.004) Copyright © 2012 The American Society of Human Genetics Terms and Conditions