Homo sapiens (Human)GPI inositol-deacylase PGAP1 117.8 kd protein in ste2-frs2 intergenic region
Comment
only n-term Pfam A PGAP1 82 302 is the alpha/beta hydrolase domain. PGAP1Involved in inositol deacylation of GPI-anchored proteins. GPI inositol deacylation may important for efficient transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi.Mutations in PGAP1 result in the disease: Mental retardation, autosomal recessive 42 (MRT42). A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Hereditary spastic paraplegias (HSPs) SPG67
(Below N is a link to NCBI taxonomic web page and E link to ESTHER at designed phylum.) > cellular organisms: NE > Eukaryota: NE > Opisthokonta: NE > Metazoa: NE > Eumetazoa: NE > Bilateria: NE > Deuterostomia: NE > Chordata: NE > Craniata: NE > Vertebrata: NE > Gnathostomata: NE > Teleostomi: NE > Euteleostomi: NE > Sarcopterygii: NE > Dipnotetrapodomorpha: NE > Tetrapoda: NE > Amniota: NE > Mammalia: NE > Theria: NE > Eutheria: NE > Boreoeutheria: NE > Euarchontoglires: NE > Primates: NE > Haplorrhini: NE > Simiiformes: NE > Catarrhini: NE > Hominoidea: NE > Hominidae: NE > Homininae: NE > Homo: NE > Homo sapiens: NE
E113Rfs_human-PGAP1 : Compound heterozygous variants in PGAP1 causing severe psychomotor retardation, brain atrophy, recurrent apneas and delayed myelination: a case report and literature review IVS10+1G>C : Compound heterozygous variants in PGAP1 causing severe psychomotor retardation, brain atrophy, recurrent apneas and delayed myelination: a case report and literature review IVS13+1G>T : Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders IVS9-2A>G_human-PGAP1 : Loss of function of PGAP1 as a cause of severe encephalopathy identified by Whole Exome Sequencing: Lessons of the bioinformatics pipeline K308NfsX25_human-PGAP1 : Cerebral visual impairment and intellectual disability caused by PGAP1 variants L197del_human-PGAP1 : Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy P92del_human-PGAP1 : Cerebral visual impairment and intellectual disability caused by PGAP1 variants Q466X_human-PGAP1 : Additional evidence that PGAP1 loss of function causes autosomal recessive global developmental delay and encephalopathy Y524X_human-PGAP1 : Additional evidence that PGAP1 loss of function causes autosomal recessive global developmental delay and encephalopathy
LegendThis sequence has been compared to family alignement (MSA) red => minority aminoacid blue => majority aminoacid color intensity => conservation rate title => sequence position(MSA position)aminoacid rate Catalytic site Catalytic site in the MSA MFLHSVNLWNLAFYVFMVFLATLGLWDVFFGFEENKCSMSYMFEYPEYQK IELPKKLAKRYPAYELYLYGEGSYAEEHKILPLTGIPVLFLPGNAGSYKQ VRSIGSIALRKAEDIDFKYHFDFFSVNFNEELVALYGGSLQKQTKFVHEC IKTILKLYKGQEFAPKSVAIIGHSMGGLVARALLTLKNFKHDLINLLITQ ATPHVAPVMPLDRFITDFYTTVNNYWILNARHINLTTLSVAGGFRDYQVR SGLTFLPKLSHHTSALSVVSSAVPKTWVSTDHLSIVWCKQLQLTTVRAFF DLIGADTKQITQNSKKKLSVLYHHFIRHPSKHFEENPAIISDLTGTSMWV
Many eukaryotic cell-surface proteins are anchored to the membrane via glycosylphosphatidylinositol (GPI). There are at least 26 genes involved in biosynthesis and remodeling of GPI anchors. Hypomorphic coding mutations in seven of these genes have been reported to cause decreased expression of GPI anchored proteins (GPI-APs) on the cell surface and to cause autosomal-recessive forms of intellectual disability (ARID). We performed homozygosity mapping and exome sequencing in a family with encephalopathy and non-specific ARID and identified a homozygous 3 bp deletion (p.Leu197del) in the GPI remodeling gene PGAP1. PGAP1 was not described in association with a human phenotype before. PGAP1 is a deacylase that removes an acyl-chain from the inositol of GPI anchors in the endoplasmic reticulum immediately after attachment of GPI to proteins. In silico prediction and molecular modeling strongly suggested a pathogenic effect of the identified deletion. The expression levels of GPI-APs on B lymphoblastoid cells derived from an affected person were normal. However, when those cells were incubated with phosphatidylinositol-specific phospholipase C (PI-PLC), GPI-APs were cleaved and released from B lymphoblastoid cells from healthy individuals whereas GPI-APs on the cells from the affected person were totally resistant. Transfection with wild type PGAP1 cDNA restored the PI-PLC sensitivity. These results indicate that GPI-APs were expressed with abnormal GPI structure due to a null mutation in the remodeling gene PGAP1. Our results add PGAP1 to the growing list of GPI abnormalities and indicate that not only the cell surface expression levels of GPI-APs but also the fine structure of GPI-anchors is important for the normal neurological development.
Human chromosome 2 is unique to the human lineage in being the product of a head-to-head fusion of two intermediate-sized ancestral chromosomes. Chromosome 4 has received attention primarily related to the search for the Huntington's disease gene, but also for genes associated with Wolf-Hirschhorn syndrome, polycystic kidney disease and a form of muscular dystrophy. Here we present approximately 237 million base pairs of sequence for chromosome 2, and 186 million base pairs for chromosome 4, representing more than 99.6% of their euchromatic sequences. Our initial analyses have identified 1,346 protein-coding genes and 1,239 pseudogenes on chromosome 2, and 796 protein-coding genes and 778 pseudogenes on chromosome 4. Extensive analyses confirm the underlying construction of the sequence, and expand our understanding of the structure and evolution of mammalian chromosomes, including gene deserts, segmental duplications and highly variant regions.
Title: Inositol deacylation of glycosylphosphatidylinositol-anchored proteins is mediated by mammalian PGAP1 and yeast Bst1p Tanaka S, Maeda Y, Tashima Y, Kinoshita T Ref: Journal of Biological Chemistry, 279:14256, 2004 : PubMed
The inositol moiety of mammalian glycosylphosphatidylinositol (GPI) is acylated at an early step in GPI biosynthesis. The inositol acylation is essential for the generation of mature GPI capable of attachment to proteins. However, the acyl group is usually absent from GPI-anchored proteins (GPI-APs) on the cell surface due to inositol deacylation that occurs in the endoplasmic reticulum (ER) soon after GPI-anchor attachment. Mammalian GPI inositol-deacylase has not been cloned, and the biological significance of the deacylation has been unclear. Here we report a GPI inositol-deacylase-deficient Chinese hamster ovary cell line established by taking advantage of resistance to phosphatidylinositol-specific phospholipase C and the gene responsible, which was termed PGAP1 for Post GPI Attachment to Proteins 1. PGAP1 encoded an ER-associated, 922-amino acid membrane protein bearing a lipase consensus motif. Substitution of a conserved putative catalytic serine with alanine resulted in a complete loss of function, indicating that PGAP1 is the GPI inositol-deacylase. The mutant cells showed a clear delay in the maturation of GPI-APs in the Golgi and accumulation of GPI-APs in the ER. Thus, the GPI inositol deacylation is important for efficient transport of GPI-APs from the ER to the Golgi.
Homo sapiens (Human) esterase D (EC 3.1.1.1) formylglutathione hydrolase