Molecular characteristics
PIGM is the catalytic component of the PIGM-PIGX complex, the mannosyltransferase I,which transfers first mannose to GlcN-(acyl)PI, generating ManGlcN-(acyl)PI in the fifth step of the GPI biosynthesis. All reported cases had the same mutation in the promoter region of PIGM. This mutation in the Sp1 binding site of the promoter region caused the defect in PIGM expression, leading to decreased expression of GPI-anchored proteins in various tissues such as neuronal tissues, vascular endothelium, skin and hematopoietic cells. Sp1 is the transcriptional factor which recruits various components that regulate trascription by acetylation, phosphorylation, and methylation of the genome DNA. As for the PIGM expression, Sp1 binding enhanced the basic transcription. Defect in Sp1 binding due to the mutation caused decreased expression of PIGM, which could be rescued by administration of HDAC inhibitor, sodium butylate, that inhibits deacetylation. These affected individuals showed no developmental delay, suggesting that this defect may be compensated with some other binding sites or other transcriptional factors during developmental stage.
Suspected pthogenecity
Mutations in the promoter region of PIGM cause decreased expression of PIGM protein, leading to decreased expression of GPI-anchored proteins. The expression levels of PIGM would be different between tissues depending on the reliance of the Sp1 binding site. Hematopoietic cells and vascular endothelial cells might be more severely affected than the other IGDs with mutations in the coding region, which caused vascular thrombosis probably because of the complement activation due to the defect in complement regulatory GPI-anchored proteins, CD59 and DAF.
Mutations (NM_145167.2)
validatad by the functional analysis and FACS analysis of blood cells and fibroblasts
c.-270G>C homo promoter GC-box
Diagnostic testing
FACS analysis of GPI-AP, CD59, CD24 and CD16 on the granulocytes can be the diagnostic testing for this PIGM deficiency. It is decreased in the affected individuals compared to that in the healthy individuals.