Abstract
Glycosylphophatidylinositol (GPI)-anchored proteins play important roles in many biological processes, and mutations affecting proteins involved in the synthesis of the GPI anchor are reported to cause a wide spectrum of intellectual disabilities (IDs) with characteristic additional phenotypic features. Here, we describe a total of five individuals (from three unrelated families) in whom we identified mutations in PGAP3, encoding a protein that is involved in GPI-anchor maturation. Three siblings in a consanguineous Pakistani family presented with profound developmental delay, severe ID, no speech, psychomotor delay, and postnatal microcephaly. A combination of autozygosity mapping and exome sequencing identified a 13.8 Mb region harboring a homozygous c.275G>A (p.Gly92Asp) variant in PGAP3 region 17q11.2-q21.32. Subsequent testing showed elevated serum alkaline phosphatase (ALP), a GPI-anchored enzyme, in all three affected children. In two unrelated individuals in a cohort with developmental delay, ID, and elevated ALP, we identified compound-heterozygous variants c.439dupC (p.Leu147Profs(∗)16) and c.914A>G (p.Asp305Gly) and homozygous variant c.314C>G (p.Pro105Arg). The 1 bp duplication causes a frameshift and nonsense-mediated decay. Further evidence supporting pathogenicity of the missense mutations c.275G>A, c.314C>G, and c.914A>G was provided by the absence of the variants from ethnically matched controls, phylogenetic conservation, and functional studies on Chinese hamster ovary cell lines. Taken together with recent data on PGAP2, these results confirm the importance of the later GPI-anchor remodelling steps for normal neuronal development. Impairment of PGAP3 causes a subtype of hyperphosphatasia with ID, a congenital disorder of glycosylation that is also referred to as Mabry syndrome.
Highlights
Glycosylphophatidylinositol (GPI)-anchored proteins play important roles in many biological processes, and mutations affecting proteins involved in the synthesis of the GPI anchor are reported to cause a wide spectrum of intellectual disabilities (IDs) with characteristic additional phenotypic features
The GPI anchor is well conserved among eukaryotes, and there are over 150 mammalian GPI-anchored proteins (GPI-APs), including receptors, adhesion molecules, and enzymes.[1]
There are around 30 genes known to be involved in the biosynthesis and remodelling of the GPI anchor, which is formed in the endoplasmic reticulum (ER), where it is attached by the GPI transamidase to a protein showing a specific C-terminal signal before it is transported to the Golgi apparatus for fatty acid remodelling and cellular export
Summary
Mutations in PGAP3 Impair GPI-Anchor Maturation, Causing a Subtype of Hyperphosphatasia with Mental Retardation. After excluding pathogenic PIGV mutations that are the most common cause of HPMRS by Sanger sequencing, we subjected DNA to enrichment of all 30 known genes associated with GPI-anchor synthesis by using a customized SureSelect library (Agilent), as well as subsequent sequencing on a HiSeq2000, as previously described.[15] Sequence variants were filtered under an autosomal-recessive model of inheritance in GeneTalk,[20] which yielded potentially pathogenic variants in PGAP3 in two individuals. Mutant PGAP3 cDNA bearing the mutation found in family A (c.275G>A [p.Gly92Asp]) either did not reduce or reduced only slightly the surface levels of three GPI-APs: CD59, CD55 (DAF), and urokinase plasminogen activator receptor (uPAR), indicating that the substitution caused a null or nearly null phenotype (Figure 3Bii).
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have