title: Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability.
abstract: PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous families. Rescue experiments with the altered proteins in PGAP2-deficient Chinese hamster ovary cell lines showed less expression of cell-surface GPI-anchored proteins DAF and CD59 than of the wild-type protein, substantiating the pathogenicity of the identified alterations. Furthermore, we observed a full rescue when we used strong promoters before the mutant cDNAs, suggesting a hypomorphic effect of the mutations. We report on alterations in the Golgi-located part of the GPI-anchor-biosynthesis pathway and extend the phenotypic spectrum of the GPI-anchor deficiencies to isolated intellectual disability with elevated ALP. GPI-anchor deficiencies can be interpreted within the concept of a disease family, and we propose that the severity of the phenotype is dependent on the location of the altered protein in the biosynthesis chain.
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, The Panum Institute, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark. lah@sund.ku.dk
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
authors.forename: Hasan
authors.initials: H
authors.lastname: Tawamie
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mang
authors.forename: Shoaib
authors.initials: S
authors.lastname: ur Rehman
authors.forename: Rebecca
authors.initials: R
authors.lastname: Buchert
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schaffer
authors.forename: Safia
authors.initials: S
authors.lastname: Muhammad
authors.forename: Mads
authors.initials: M
authors.lastname: Bak
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Eric P
authors.initials: EP
authors.lastname: Bennett
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Maeda
authors.forename: Michael
authors.initials: M
authors.lastname: Aigner
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.forename: Shahid Mahmood
authors.initials: SM
authors.lastname: Baig
authors.forename: Rami
authors.initials: R
authors.lastname: Abou Jamra
mesh_terms: D000469:Alkaline Phosphatase / Q000097:blood; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002648:Child; D002675:Child, Preschool; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D017261:Glycosylphosphatidylinositols / Q000235:genetics*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: D017261:Glycosylphosphatidylinositols; D009687:Nuclear Proteins; C484441:PGAP2 protein, human; D000469:Alkaline Phosphatase
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