Molecular characteristics

Molecular characteristics
Biogenesis of GPI-anchored proteins is a conserved post-translational mechanism in eukaryotes and is important for attaching these proteins to the cell membrane, for protein sorting, trafficking, and dynamics. There are at least 27 genes involved in biosynthesis and remodelling of GPI anchors. PIGL encodes a PIGL protein involved in the second step of GPI biosynthesis, so mutations in PIGL cause decreased expression levels of GPI-anchored proteins.

Mutations (NM_004278.3)
c.36_48del(p.Leu13Alafs*11)/ c.254_255del(p.Glu86Aspfs*2)
c.48G>A (p.Trp16*)/ c.336-2A>G (g.IVS2 -2A>G)
c.60G>A (p.Trp20*) / c.262C>T (p.Arg88Cys)
c.347_355del (p.Asp116_Pro118del homo
c.500T>C (p.Leu167Pro)/ c.274delC (p.Leu92Phefs*15)
c.500T>C (p.Leu167Pro)/c.652C>T (p.Gln218*)
c.500T>C (p.Leu167Pro) homo
c.500T>C (p.Leu167Pro)/ p.427-1G>A(g.IVS3-1G>A)
c.500T>C (p.Leu167Pro)/ c.del17p12-p11.2
c.500T>C (p.Leu167Pro)/ 14.4kbdel(ex4-6)
c.500T>C (p.Leu167Pro)/del 802bp involving the 5’ UTR and the 50 AA, including the ATG in exon 1
c.701G>A (p.Arg234His)/ ex3 del

Suspected pathophysiologic mechanism
The PIGL gene is involved in the second step of GPI biosynthesis, so PIGL deficient cells express decreased levels of GPI-anchored proteins. GPI-anchored proteins play vital roles in numerous biological processes, such as neuronal development. The decreased levels of GPI-anchored proteins cause abnormal neuronal development which can lead to intellectual disability, developmental delay, and epilepsy.

Diagnostic testing
FACS analysis of a GPI-anchored protein, CD16 on the granulocytes can be the diagnostic testing for PIGL deficiency. It is decreased in the affected individuals compared to that in the healthy individuals. Affected individuals are partially deficient in PIGL activity, so levels of some GPI-anchored proteins such as CD59 and DAF are often within normal ranges.