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

Zhao, Jin James, 1983- (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab,Lars Feuk

Halvardson, Jonatan, 1982- (author): Uppsala universitet,Medicinsk genetik och genomik,Science for Life Laboratory, SciLifeLab

Knaus, Alexej (author)

Georgii-Hemming, Patrik (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab,Karolinska Institute

Krawitz, Peter (author)

Thuresson, Ann-Charlotte (author): Uppsala universitet,Medicinsk genetik och genomik

Feuk, Lars (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik

(creator_code:org_t)

2017-06-12
2017
English.
In: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 38:10, s. 1394-1401

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Abstract Subject headings

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.

By the author/editor: Zhao, Jin James, ...; Halvardson, Jona ...; Knaus, Alexej; Georgii-Hemming, ...; Baeck, Peter; Krawitz, Peter; show more...; Thuresson, Ann-C ...; Feuk, Lars; show less...

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