Pigg-KO Mouse

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/