Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation.
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.
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, Berlin, Germany.
Peter M
PM
Krawitz
Yoshiko
Y
Murakami
Jochen
J
Hecht
Ulrike
U
Krüger
Susan E
SE
Holder
Geert R
GR
Mortier
Barbara
B
Delle Chiaie
Elfride
E
De Baere
Miles D
MD
Thompson
Tony
T
Roscioli
Szymon
S
Kielbasa
Taroh
T
Kinoshita
Stefan
S
Mundlos
Peter N
PN
Robinson
Denise
D
Horn
D000293:Adolescent; D000469:Alkaline Phosphatase / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D013577:Syndrome
D008565:Membrane Proteins; C485854:PIGO protein, human; D000469:Alkaline Phosphatase