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Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons50196

Hecht,  J.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Berlin Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50380

Kielbasa,  S. M.
Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50437

Mundlos,  S.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Berlin Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin;
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50496

Robinson,  P. N.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Berlin Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin;
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin;

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Krawitz.pdf
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Zitation

Krawitz, P. M., Murakami, Y., Hecht, J., Kruger, U., Holder, S. E., Mortier, G. R., et al. (2012). Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation. American Journal of Human Genetics, 91(1), 146-151. doi:10.1016/j.ajhg.2012.05.004.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-000E-F270-E
Zusammenfassung
Hyperphosphatasia with mental retardation syndrome (HPMRS), an autosomal-recessive form of intellectual disability characterized by facial dysmorphism, seizures, brachytelephalangy, and persistent elevated serum alkaline phosphatase (hyperphosphatasia), was recently shown to be caused by mutations in PIGV, a member of the glycosylphosphatidylinositol (GPI)-anchor-synthesis pathway. However, not all individuals with HPMRS harbor mutations in this gene. By exome sequencing, we detected compound-heterozygous mutations in PIGO, a gene coding for a membrane protein of the same molecular pathway, in two siblings with HPMRS, and we then found by Sanger sequencing further mutations in another affected individual; these mutations cosegregated in the investigated families. The mutant transcripts are aberrantly spliced, decrease the membrane stability of the protein, or impair enzyme function such that GPI-anchor synthesis is affected and the level of GPI-anchored substrates localized at the cell surface is reduced. Our data identify PIGO as the second gene associated with HPMRS and suggest that a deficiency in GPI-anchor synthesis is the underlying molecular pathomechanism of HPMRS.