|
Title
|
|
|
|
Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| 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. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
The American journal of human genetics / American Society of Human Genetics [Bethesda, Md] - New York, N.Y., 1949, currens
| |
|
Publication
|
|
|
|
New York, N.Y.
:
2012
| |
|
ISSN
|
|
|
|
0002-9297
[print]
1537-6605
[online]
| |
|
DOI
|
|
|
|
10.1016/J.AJHG.2012.05.004
| |
|
Volume/pages
|
|
|
|
91
:1
(2012)
, p. 146-151
| |
|
ISI
|
|
|
|
000306445000012
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (open access)
|
|
|
|
| |
|