PIGG, or Phosphatidylinositol Glycan Anchor Biosynthesis, class G, is an ethanolamine phosphate transferase. It catalyzes the modification of glycosylphosphatidylinositol (GPI), which serves as an anchor for surface proteins called GPI-anchored proteins (GPI-APs) on the cell membrane. The GPI-anchor biosynthesis pathway in which PIGG is involved is crucial for the proper functioning of cells, and its disruption can lead to various biological consequences [1,2,4].

Pathogenic biallelic variants in PIGG cause inherited GPI deficiency (IGD). Phenotypic analysis of individuals with such variants shows shared PIGG deficiency-associated features. Those with null or severely decreased PIGG activity present with cerebellar atrophy, various neurological manifestations, mitochondrial dysfunction, in addition to classic IGD symptoms like hypotonia, intellectual disability/developmental delay, and seizures. Individuals with mildly decreased activity show autism spectrum disorder. In vitro studies in a PIGG/PIGO double-knockout system demonstrated enzymatic activity defects for PIGG variants, validating the pathogenicity of these variants and helping to study PIGG physiological functions [1]. Recessive variants in PIGG also cause a motor neuropathy with variable conduction block, childhood tremor, and febrile seizures, expanding the known phenotype associated with PIGG [3]. The Emm negative blood group status is associated with a rare deficiency of PIGG, potentially defining a new Emm blood group system [2].

In conclusion, PIGG is essential for the modification of GPI in the GPI-anchor biosynthesis pathway. Research using knockout systems has been valuable in revealing its role in multiple disease conditions, including IGD, motor neuropathy, and potentially blood group-related phenotypes. Understanding PIGG's function through these models helps in clarifying the underlying mechanisms of these diseases and may aid in developing targeted therapies.

References:

1. Tremblay-Laganière, Camille, Maroofian, Reza, Nguyen, Thi Tuyet Mai, Campeau, Philippe M, Murakami, Yoshiko. 2021. PIGG variant pathogenicity assessment reveals characteristic features within 19 families. In Genetics in medicine : official journal of the American College of Medical Genetics, 23, 1873-1881. doi:10.1038/s41436-021-01215-9. https://pubmed.ncbi.nlm.nih.gov/34113002/

2. Lane, William J, Aeschlimann, Judith, Vege, Sunitha, Joshi, Sanmukh R, Westhoff, Connie M. 2021. PIGG defines the Emm blood group system. In Scientific reports, 11, 18545. doi:10.1038/s41598-021-98090-w. https://pubmed.ncbi.nlm.nih.gov/34535746/

3. Record, Christopher J, O'Connor, Antoinette, Verbeek, Nienke E, Murphy, Sinéad M, Reilly, Mary M. 2024. Recessive Variants in PIGG Cause a Motor Neuropathy with Variable Conduction Block, Childhood Tremor, and Febrile Seizures: Expanding the Phenotype. In Annals of neurology, 97, 388-396. doi:10.1002/ana.27113. https://pubmed.ncbi.nlm.nih.gov/39444079/

4. Makrythanasis, Periklis, Kato, Mitsuhiro, Zaki, Maha S, Antonarakis, Stylianos E, Murakami, Yoshiko. 2016. Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia. In American journal of human genetics, 98, 615-26. doi:10.1016/j.ajhg.2016.02.007. https://pubmed.ncbi.nlm.nih.gov/26996948/