PIGK gene, encoding a key component of glycosylphosphatidylinositol (GPI) transamidase, was recently reported to be associated with inherited GPI deficiency disorders (IGDs). However, little is known about the specific downstream effects of PIGK on neurodevelopment due to the rarity of the disease and the lack of in vivo study. Here, we described 2 patients in a Chinese family presented with profound global developmental delay, severe hypotonia, seizures, and postnatal progressive global brain atrophy including hemisphere, cerebellar and corpus callosum atrophy. Two novel compound heterozygous variants in PIGK were identified via genetic analysis, which was proved to cause significant decrease of PIGK protein and reduced cell surface presence of GPI-APs in the patients. To explore the role of Pigk on embryonic and neuronal development, we constructed Pigk knock-down zebrafish and knock-in mouse models. Zebrafish injected with a small dose of morpholino oligonucleotides displayed severe developmental defects including small eyes, deformed head, curly spinal cord, and unconsumed yolk sac. Primary motor neuronal dysplasia and extensive neural cell apoptosis were further observed. Meanwhile, the mouse models, carrying the two variants respectively homologous with the patients, both resulted in complete embryonic lethality of the homozygotes, which suggested the intolerable effect caused by amino acid substitution of Asp204 as well as the truncated mutation. Our findings provide the in vivo evidence for the essential role of PIGK during the embryonic and neuronal development. Based on these data, we propose a basis for further study of pathological and molecular mechanisms of PIGK-related neurodevelopmental defects.
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We acknowledge the generous support from the families included in this article. We are grateful to Dr. Hu Tan for help with case data collected and Dr. Lanlan Zeng for useful experimental advice.
This work was supported by the grants from the National Key R&D Program of China (2018YFC1002201, 2017YFC1001802, 2019YFA0405603), the National Natural Science Foundation of China (81974240, 81970829, 81771599), the Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defects in Hunan Province (2019SK1010, 2019SK1014) and the Key Research and Development Plan Program of Anhui Province (202004j07020020).
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The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Research Ethics Committee of Hunan Jiahui Genetics Hospital. The animal manipulations were conducted in strict accordance with the guidelines and regulations set forth by Central South University (CSU) Animal Resources Center and University Animal Care and Use Committee and University of Science and Technology of China (USTC) Animal Resources Center and University Animal Care and Use Committee respectively.
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Chen, X., Yin, W., Chen, S. et al. Loss of PIGK function causes severe infantile encephalopathy and extensive neuronal apoptosis. Hum Genet 140, 791–803 (2021). https://doi.org/10.1007/s00439-020-02243-2