A novel homozygous variant of the PIGK gene caused by paternal disomy in a patient with neurodevelopmental disorder, cerebellar atrophy, and seizures

• Published in: Journal of human genetics Vol. 69; no. 11; pp. 553 - 563
• Main Authors: Sadamitsu, Kenichiro, Yanagi, Kumiko, Hasegawa, Yuiko, Murakami, Yoshiko, Low, Sean E., Ooshima, Daikun, Matsubara, Yoichi, Okamoto, Nobuhiko, Kaname, Tadashi, Hirata, Hiromi
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01-11-2024; Nature Publishing Group
• Subjects: 45; 45/43; 631/208/1516/1510; 692/420/2489/144; 692/699/375; Atrophy; Attachment; Biomedical and Life Sciences; Biomedicine; Brachydactyly; Cell surface; Cerebellum; Channel gating; Danio rerio; Endoplasmic reticulum; Gene Expression; Gene Function; Gene Therapy; Glycosylphosphatidylinositol; Hearing loss; Human Genetics; Localization; Molecular Medicine; Neurodevelopmental disorders; Neurogenesis; Proteins; Seizures; Sodium channels (voltage-gated); Zygosity
• ISSN: 1434-5161; 1435-232X; 1435-232X
• DOI: 10.1038/s10038-024-01264-3

Glycosylphosphatidylinositol (GPI)-anchored proteins are located at the cell surface by a covalent attachment between protein and GPI embedded in the plasma membrane. This attachment is catalyzed by GPI transamidase comprising five subunits (PIGK, PIGS, PIGT, PIGU, and GPAA1) in the endoplasmic reticulum. Loss of either subunit of GPI transamidase eliminates cell surface localization of GPI-anchored proteins. In humans, pathogenic variants in either subunit of GPI transamidase cause neurodevelopmental disorders. However, how the loss of GPI-anchored proteins triggers neurodevelopmental defects remains largely unclear. Here, we identified a novel homozygous variant of
PIGK
, NM_005482:c.481A > G,p. (Met161Val), in a Japanese female patient with neurodevelopmental delay, hypotonia, cerebellar atrophy, febrile seizures, hearing loss, growth impairment, dysmorphic facial features, and brachydactyly. The missense variant was found heterozygous in her father, but not in her mother. Zygosity analysis revealed that the homozygous
PIGK
variant in the patient was caused by paternal isodisomy. Rescue experiments using
PIGK
-deficient CHO cells revealed that the p.Met161Val variant of PIGK reduced GPI transamidase activity. Rescue experiments using
pigk
mutant zebrafish confirmed that the p.Met161Val variant compromised PIGK function in tactile-evoked motor response. We also demonstrated that axonal localization of voltage-gated sodium channels and concomitant generation of action potentials were impaired in
pigk
-deficient neurons in zebrafish, suggesting a link between GPI-anchored proteins and neuronal defects. Taken together, the missense p.Met161Val variant of
PIGK
is a novel pathogenic variant that causes the neurodevelopmental disorder.