Targeted sequencing of GPI anchor synthesis pathway genes identifies a new causal genes of hyperphosphatasia with mental retardation. P. Krawitz1, Y. Murakami2, A. Riess4, M. Hietala3, U. Krueger1, N. Zhu1, T. Kinoshita2, S. Mundlos1, J. Hecht1, P. Robinson1, D. Horn1 1) Medical Genetics, Charité, Berlin, Berlin, Germany; 2) Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka, Japan; 3) Medical Biochemistry and Genetics, University, Turku, Turku, Finland; 4) Institute for Human Genetics, Eberhard Karls University Tuebingen, Tuebingen, Germany.

   Recently, genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor came into the spotlight as a new subclass of congenital disorders of glycosylation (CDG) with a characteristic spectrum of clinical features. Up to date mutations in six genes of the GPI-anchor synthesis pathway, PIGA, PIGL, PIGM, PIGN, PIGO, and PIGV have been identified in patients with severe neurological features including seizures, muscular hypotonia, and intellectual disability. We developed a diagnostic gene panel for targeting all known genes of the GPI-anchor synthesis pathway to screen patients matching these features. By this means we detected three missense mutations in PGAP2, c.46C>T, c.380T>C, and c.479C>T in two unrelated patients with hyperphosphatasia mental retardation syndrome (HPMRS). These mutations cosegregated in the investigated families. PGAP2 is a gene coding for an acyltransferase that is involved in fatty acid remodeling of the GPI-anchor that is required for Golgi transport of GPIlinked substrates. Transfection of the mutant constructs p.Arg16Trp, 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 also an impairment of GPI-anchor remodeling causes HPMRS and conclude that targeted sequencing of the GPI-anchor pathway genes is an effective diagnostic approach for a subclass of CDGs.

You may contact the first author (during and after the meeting) at