Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation.
Am J Hum Genet
; 91(1): 146-51, 2012 Jul 13.
Article
in En
| MEDLINE
| ID: mdl-22683086
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Alkaline Phosphatase
/
Membrane Proteins
/
Intellectual Disability
/
Mutation
Type of study:
Prognostic_studies
Limits:
Adolescent
/
Child
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Child, preschool
/
Female
/
Humans
/
Infant
Language:
En
Journal:
Am J Hum Genet
Year:
2012
Document type:
Article
Affiliation country:
Germany