Molecular characteristics

Many eukaryotic cell-surface proteins are anchored to the membrane via glycosylphosphatidylinositol (GPI). There are at least 27 genes involved in biosynthesis and remodeling of GPI anchors. Hypomorphic coding mutations in twenty of these genes have been reported to cause decreased expression of GPI anchored proteins (GPI-APs) on the cell surface or expression with abnormal structures of GPI-anchor and to cause autosomal-recessive forms of intellectual disability. They are called inherited GPI deficiencies (IGDs).

PIGK is a subunit of the GPI transamidase complex that catalyzes the attachment of preformed GPI to proteins containing a C-terminal GPI attachment site. It encodes a member of the cysteine protease family C13 that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. Homozygous or compound heterozygous mutations in the PIGK gene were identified in 12 patients from 9 unrelated families with NEDHCAS. The mutations, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. There were missense, nonsense, and splice site mutations, although none of the patients were homozygous for a nonsense or splice site mutation.

Flow cytometric analysis of available patient peripheral blood cells showed variably decreased cell surface expression (5 to 35% of controls) of GPI-anchored proteins, particularly CD16 (see 146740), as well as decreased cell-surface expression of FLAER, a marker for all GPI-anchored proteins. In vitro functional expression studies in PIGK-deficient CHO cells showed that 2 of the missense variants (C275R, 605087.0001 and S53F, 605087.0002) were unable to fully rescue the GPI-anchor defect, suggesting that they are loss-of-function or hypomorphic alleles. Approximately one in every 200 mammalian proteins is a GPI-anchored proteins (GPI-Aps). These proteins are important for neurological development and function, embryogenesis, immune response, and signal transduction.