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Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency

Abstract

Attachment to the plasma membrane by linkage to a glycosylphosphatidylinositol (GPI) anchor1 is a mode of protein expression highly conserved from protozoa to mammals2. As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells3,4. We have identified a novel disease characterized by a propensity to venous thrombosis and seizures in which deficiency of GPI is inherited in an autosomal recessive manner. In two unrelated kindreds, a point mutation (c → g) at position −270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif. This mutation substantially reduces transcription of PIGM and blocks mannosylation of GPI, leading to partial but severe deficiency of GPI. These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function.

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Figure 1: Pedigree analysis and cell-surface expression of GPI-anchored proteins in inherited GPI deficiency.
Figure 2: Identification of the candidate disease gene.
Figure 3: PIGM is the disease gene in inherited GPI deficiency.
Figure 4: Functional analysis of the −270c → g substitution.

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Acknowledgements

We would like to thank D. Araten and R. Notaro for providing the N+ and N− LBCLs; T. Vulliamy and A. Marrone for providing DNA samples and help with the EMSAs, respectively; and I. Dokal, J. Melo, T. Vulliamy, M. Hu and E. Spanoudakis for critical reading of the manuscript. We also thank L. Luzzatto for continuous support and inspiration. A. Almeida is a Leukaemia Research Fund Clinical Research Fellow and A. Karadimitris is a Leukaemia Research Fund Bennett Senior Fellow. T. Kinoshita, Y. Murakami and Y. Maeda are supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Correspondence to Anastasios Karadimitris.

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Supplementary information

Supplementary Fig. 1

Genome-wide search for the identification of disease gene in inherited GPI deficiency. (PDF 112 kb)

Supplementary Fig. 2

GPI expression in the cell lines used in the biochemical experiments. (PDF 110 kb)

Supplementary Fig. 3

Restriction enzyme confirmation of the genotypes at position −270. (PDF 91 kb)

Supplementary Table 1

Clinical features of children with inherited GPI deficiency. (PDF 27 kb)

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Almeida, A., Murakami, Y., Layton, D. et al. Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency. Nat Med 12, 846–851 (2006). https://doi.org/10.1038/nm1410

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