title: PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome.
abstract: Recently, mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor have been identified in a new subclass of congenital disorders of glycosylation (CDGs) with a distinct spectrum of clinical features. To date, mutations have been identified in six genes (PIGA, PIGL, PIGM, PIGN, PIGO, and PIGV) encoding proteins in the GPI-anchor-synthesis pathway in individuals with severe neurological features, including seizures, muscular hypotonia, and intellectual disability. We developed a diagnostic gene panel for targeting all known genes encoding proteins in the GPI-anchor-synthesis pathway to screen individuals matching these features, and we detected three missense mutations in PGAP2, c.46C>T, c.380T>C, and c.479C>T, in two unrelated individuals with hyperphosphatasia with mental retardation syndrome (HPMRS). The mutations cosegregated in the investigated families. PGAP2 is involved in fatty-acid GPI-anchor remodeling, which occurs in the Golgi apparatus and is required for stable association between GPI-anchored proteins and the cell-surface membrane rafts. Transfection of the altered protein constructs, p.Arg16Trp (NP_001243169.1), p.Leu127Ser, and p.Thr160Ile, into PGAP2-null cells showed only partial restoration of GPI-anchored marker proteins, CD55 and CD59, on the cell surface. In this work, we show that an impairment of GPI-anchor remodeling also causes HPMRS and conclude that targeted sequencing of the genes encoding proteins in the GPI-anchor-synthesis pathway is an effective diagnostic approach for this subclass of CDGs.
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, 13353 Berlin, Germany.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Krawitz
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.forename: Angelika
authors.initials: A
authors.lastname: Rieß
authors.forename: Marja
authors.initials: M
authors.lastname: Hietala
authors.forename: Ulrike
authors.initials: U
authors.lastname: Krüger
authors.forename: Na
authors.initials: N
authors.lastname: Zhu
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000097:blood; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D017261:Glycosylphosphatidylinositols / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010760:Phosphorus Metabolism Disorders / Q000235:genetics* / Q000473:pathology; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
chemical_list: D017261:Glycosylphosphatidylinositols; D009687:Nuclear Proteins; C484441:PGAP2 protein, human; D000469:Alkaline Phosphatase
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