Mutations in PIGO, a Member of the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation
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- 作者：Peter?M. Krawitz ; Yoshiko Murakami ; Jochen Hecht ; Ulrike Kr¨¹ger ; Susan?E. Holder ; Geert?R. Mortier ; Barbara Delle?Chiaie ; Elfride De?Baere ; Miles?D. Thompson ; Tony Roscioli ; Szymon Kielbasa ; Taroh Kinoshita ; Stefan Mundlos ; Peter?N. Robinson ; Denise Horn
- 刊名：The American Journal of Human Genetics
- 出版年：2012
- 出版时间：13 July, 2012
- 年：2012
- 卷：91
- 期：1
- 页码：146-151
- 全文大小：635 K
文摘
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.