RRC ID 70875
著者 Chen X, Yin W, Chen S, Zhang W, Li H, Kuang H, Zhou M, Teng Y, Zhang J, Shen G, Liang D, Li Z, Hu B, Wu L.
タイトル Loss of PIGK function causes severe infantile encephalopathy and extensive neuronal apoptosis.
ジャーナル Hum Genet
Abstract 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.
巻・号 140(5)
ページ 791-803
公開日 2021-5-1
DOI 10.1007/s00439-020-02243-2
PII 10.1007/s00439-020-02243-2
PMID 33392778
MeSH Abnormalities, Multiple / genetics Animals Apoptosis / genetics Brain Diseases / genetics* Cell Adhesion Molecules / genetics* Cell Line Child, Preschool Disease Models, Animal Embryonic Development / genetics Gene Knock-In Techniques Glycosylphosphatidylinositols / deficiency* Glycosylphosphatidylinositols / genetics Humans Male Mice Mice, Inbred C57BL Mice, Transgenic Nervous System Malformations / genetics* Neurogenesis / genetics* Seizures / genetics* Zebrafish
IF 5.743
リソース情報
ゼブラフィッシュ Tol-056