Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases

Abstract

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.

Biosynthesis and biology of mammalian GPI-anchored proteins

“…Twenty-one genes whose mutations caused IGD cover almost all steps in the biosynthesis of the core GPI, its transfer to proteins and maturation of the GPI, for which genes are known except a step mediated by PGAP5 [140][141][142][143][144][145][146]149,151,153,158,161]. It seems, therefore, that every step in GPI-AP biogenesis is critical for human health.…”

Lamin is essential for nuclear localization of the GPI synthesis enzyme PIG-B and GPI-anchored protein production in Drosophila

“…Ten mutations of the human PIGB gene were recently reported to cause inherited GPI deficiencies characterized by axonal neuropathy and metabolic abnormalities (Murakami et al, 2019). Among these ten mutations, the PIGB A388P mutant exhibits severe defects.…”

A CRISPR-Cas9–engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions

“…However, most patients, including the recently described cases that are due to GPIBD20 and GPIBD21, exhibit intellectual disability, psychomotor delay and epilepsy (5,6). Furthermore, due to residual function of GPI anchor synthesis, patient-derived fibroblasts display a reduced number of GPI-linked proteins on the cell surface (7).…”