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. 2017 Oct;38(10):1394-1401.
doi: 10.1002/humu.23268. Epub 2017 Jun 12.

Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function

Jin James Zhao  1 , Jonatan Halvardson  1 , Alexej Knaus  2   3 , Patrik Georgii-Hemming  1   4 , Peter Baeck  5 , Peter M Krawitz  2 , Ann-Charlotte Thuresson  1   6 , Lars Feuk  1
Affiliations

Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function

Jin James Zhao et al. Hum Mutat. 2017 Oct.

Abstract

Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism. Here, we present two siblings with ID, cerebellar hypoplasia, cerebellar ataxia, early-onset seizures, and minor facial dysmorphology. Using exome sequencing, we identified a homozygous nonsense variant (NM_001127178.1:c.1640G>A, p.Trp547*) in the gene Phosphatidylinositol Glycan Anchor Biosynthesis, Class G (PIGG) in both the patients. Variants in several other GPI anchor synthesis genes lead to a reduced expression of GPI-anchored proteins (GPI-APs) that can be measured by flow cytometry. No significant differences in GPI-APs could be detected in patient granulocytes, consistent with recent findings. However, fibroblasts showed a reduced global level of GPI anchors and of specific GPI-linked markers. These findings suggest that fibroblasts might be more sensitive to pathogenic variants in GPI synthesis pathway and are well suited to screen for GPI-anchor deficiencies. Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an ID syndrome, and we find that loss of function of PIGG is associated with GPI deficiency.

Keywords: GPI deficiency; PIGG; exome sequencing; intellectual disability.

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Figures

Figure 1
Figure 1
A: Pedigree of the family. Patient II:2 (B, C) and patient II:3 (D, E) at the age of 9 and 7 years, respectively
Figure 2
Figure 2
GPI anchors and protein levels of GPI‐anchored markers CD55, CD59, CD73, and CD90 are reduced on fibroblast cell surfaces in affected siblings compared with healthy parents. Measurements were performed in triplicates. Significant reduction of marker expression was assessed with a t‐test, P ≤ 0.05 are marked with *; P ≤ 0.01 are marked with **
Figure 3
Figure 3
A: PIGG transcript levels are significantly lower in the two patients compared with their parents. B: Sanger sequencing of the variant in the heterozygous parents shows that the levels of mutated allele are very low, indicating that the transcripts with the mutation are degraded by nonsense‐mediated decay
Figure 4
Figure 4
Relative fold change in the expression between patients and parents for genes in the GPI synthesis pathway. PIGG stands out by showing a significant reduction in the patients
See this image and copyright information in PMC

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