Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome.
HPMRS or Mabry syndrome is a heterogeneous glycosylphosphatidylinositol (GPI) anchor deficiency that is caused by an impairment of synthesis or maturation of the GPI-anchor. The expressivity of the clinical features in HPMRS varies from severe syndromic forms with multiple organ malformations to mild nonsyndromic intellectual disability. In about half of the patients with the clinical diagnosis of HPMRS, pathogenic mutations can be identified in the coding region in one of the six genes, one among them is PGAP3. In this work, we describe a screening approach with sequence specific baits for transcripts of genes of the GPI pathway that allows the detection of functionally relevant mutations also including introns and the 5' and 3' UTR. By this means, we also identified pathogenic noncoding mutations, which increases the diagnostic yield for HPMRS on the basis of intellectual disability and elevated serum alkaline phosphatase. In eight affected individuals from different ethnicities, we found seven novel pathogenic mutations in PGAP3. Besides five missense mutations, we identified an intronic mutation, c.558-10G>A, that causes an aberrant splice product and a mutation in the 3'UTR, c.*559C>T, that is associated with substantially lower mRNA levels. We show that our novel screening approach is a useful rapid detection tool for alterations in genes coding for key components of the GPI pathway.
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany.|Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, Berlin, 14195, Germany.|Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité Campus Virchow Klinikum, Augustenburger Platz 1, Berlin, 13353, Germany.
Alexej
A
Knaus
Department of Pediatrics, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, 6068507, Japan.
Tomonari
T
Awaya
Division of Child Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104-4399.|Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel 24105, Germany.
Ingo
I
Helbig
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Zaid
Z
Afawi
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel 24105, Germany.
Manuela
M
Pendziwiat
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Jubran
J
Abu-Rachma
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Miles D
MD
Thompson
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
David E
DE
Cole
Greenwood Genetic Center, Greenwood, South Carolina.
Steve
S
Skinner
Greenwood Genetic Center, Greenwood, South Carolina.
Fran
F
Annese
North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, HA1 3UJ, UK.
Natalie
N
Canham
Epigenomics and Tumor Genetics, CCG, University of Cologne, Cologne, 50931, Germany.
Michal R
MR
Schweiger
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany.|Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, Berlin, 14195, Germany.
Peter N
PN
Robinson
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany.|Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, Berlin, 14195, Germany.
Stefan
S
Mundlos
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, 565, Japan.|World Premier International Immunology Frontier Research Center, Osaka University, Osaka, 565, Japan.
Taroh
T
Kinoshita
Hôpital Necker - Enfants Malades, Unité INSERM 781, Laboratoire de génétique moléculaire Tour Lavoisier - 2ème étage, Paris Cedex, 15 75743, France.
Arnold
A
Munnich
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, 565, Japan.|World Premier International Immunology Frontier Research Center, Osaka University, Osaka, 565, Japan.
Yoshiko
Y
Murakami
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany.
Denise
D
Horn
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany.|Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, Berlin, 14195, Germany.
Peter M
PM
Krawitz
D020413:3' Untranslated Regions; D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology*; D000293:Adolescent; D000328:Adult; D002265:Carboxylic Ester Hydrolases; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology*; D007438:Introns; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010760:Phosphorus Metabolism Disorders / Q000235:genetics* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
D020413:3' Untranslated Regions; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D002265:Carboxylic Ester Hydrolases; C476212:PGAP3 protein, human
Mabry syndrome; PGAP3; hyperphosphatasia with mental retardation; intellectual disability; noncoding mutations