in several families, whose homozygous members showed global developmental delay, severe intellectual disability, muscle weakness, and behavioral abnormalities like Rett syndrome7). All these symptoms overlap with those of PIGG-IGD. Likewise, NT5E/CD73, which is widely expressed in brain tissue cells, might account for some of brain related abnormalities. This enzyme is known to convert AMP to adenosine. Functions of NT5E/CD73 in the central nervous system include roles in locomotion and behavior, memory and plasticity, sleep regulation, and thermoregulation8). GPI transamidase (GPIT) complex, consisting of PIGK, GPAA1, PIGT, PIGU, and PIGS catalyzes the cleavage of the C-terminal signal peptide of GPI precursor proteins between the ω and ω+1 amino acids, and the formation of an amide bond between the ω amino acid carboxyl group and EthN of GPI9).ReferencesThere arise two questions. The one is, how GPIT targets the precursor protein to EthN-P on Man2 or Man3 in wild type cells? It might be that some precursor proteins are conformationally more fit to the Man2-linked EthN-P. Alternatively, it is also possible that the conformation of the enzyme complex changes depending upon the precursor protein, setting the target preference. Structural analysis of enzyme dead GPIT complex together with NT5E precursor protein would solve this important question. The other is, what could be the functional difference between the two structures of GPI-APs? Each GPI-AP works as a receptor, a ligand, an adhesion molecule, or as an enzyme. It is very possible that binding partners end up with different binding affinities to the GPI-APs with the alternate structure.1) Kinoshita T. Biosynthesis and biology of mammalian GPI-anchored proteins. Open Biol 10: 190290, 2020 2) Kuki I. et al. Case report on vitamin B6 responsive epilepsy due to inherited GPI deficiency. Neurology 81: 1467-1469, 20133) Salian S. et al. Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins. Clin Genet. 100(5):607-614, 20214) Baratang NV. et al. Inherited glycophosphatidylinositol deficiency variant database and analysis of pathogenic variants. Mol Genet Genomic Med. 7 (7):e00743. 20195) Makrythanasis P et al .Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia. Am J Hum Genet 98: 615-626, 20166) Tremblay-Laganière C. et al. PIGG variant pathogenicity assessment reveals characteristic features within 19 families. Genet Med, Oct;23(10):1873-1881, 20217) Heimer G. et al. Netrin-G2 dysfunction causes a Rett-like phenotype with areflexia. Hum Mutat 41: 476-486, 20208) Minor M. et al. Cell type- and tissue-specific functions of ecto-5'-nucleotidase (CD73). Am J Physiol Cell Physiol 317: C1079-C1092, 20199) Eisenhaber B. et al. Transamidase subunit GAA1/GPAA1 is a M28 family metallo-peptide-synthetase that catalyzes the peptide bond formation between the substrate protein's omega-site and the GPI lipid anchor's phosphoethanolamine. Cell Cycle 13: 1912-1917, 201497
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