Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation.
Glycosylphophatidylinositol (GPI)-anchored proteins play important roles in many biological processes, and mutations affecting proteins involved in the synthesis of the GPI anchor are reported to cause a wide spectrum of intellectual disabilities (IDs) with characteristic additional phenotypic features. Here, we describe a total of five individuals (from three unrelated families) in whom we identified mutations in PGAP3, encoding a protein that is involved in GPI-anchor maturation. Three siblings in a consanguineous Pakistani family presented with profound developmental delay, severe ID, no speech, psychomotor delay, and postnatal microcephaly. A combination of autozygosity mapping and exome sequencing identified a 13.8 Mb region harboring a homozygous c.275G>A (p.Gly92Asp) variant in PGAP3 region 17q11.2-q21.32. Subsequent testing showed elevated serum alkaline phosphatase (ALP), a GPI-anchored enzyme, in all three affected children. In two unrelated individuals in a cohort with developmental delay, ID, and elevated ALP, we identified compound-heterozygous variants c.439dupC (p.Leu147Profs(∗)16) and c.914A>G (p.Asp305Gly) and homozygous variant c.314C>G (p.Pro105Arg). The 1 bp duplication causes a frameshift and nonsense-mediated decay. Further evidence supporting pathogenicity of the missense mutations c.275G>A, c.314C>G, and c.914A>G was provided by the absence of the variants from ethnically matched controls, phylogenetic conservation, and functional studies on Chinese hamster ovary cell lines. Taken together with recent data on PGAP2, these results confirm the importance of the later GPI-anchor remodelling steps for normal neuronal development. Impairment of PGAP3 causes a subtype of hyperphosphatasia with ID, a congenital disorder of glycosylation that is also referred to as Mabry syndrome.
National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
Malcolm F
MF
Howard
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Yoshiko
Y
Murakami
National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
Alistair T
AT
Pagnamenta
Pränatal-Medizin München, 80637 München, Germany.
Cornelia
C
Daumer-Haas
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Björn
B
Fischer
Berlin Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Jochen
J
Hecht
Research Institute of Molecular Pathology, 1030 Vienna, Austria.
David A
DA
Keays
National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
Samantha J L
SJ
Knight
Institute of Medical Immunology, Charité Universitätsmedizin, 13353 Berlin, Germany.
Uwe
U
Kölsch
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, 13353 Berlin, Germany.
Ulrike
U
Krüger
Department of Pediatrics, Klinikum Dritter Orden, 80638 München, Germany.
Steffen
S
Leiz
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Yusuke
Y
Maeda
Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, TN 37232-2578, USA.
Daphne
D
Mitchell
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, 13353 Berlin, Germany; Berlin Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Stefan
S
Mundlos
Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, TN 37232-2578, USA.
John A
JA
Phillips
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, 13353 Berlin, Germany; Berlin Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Peter N
PN
Robinson
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, OX3 9DU Oxford, UK. Electronic address: usha.kini@ouh.nhs.uk.
Usha
U
Kini
National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
Jenny C
JC
Taylor
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, 13353 Berlin, Germany.
Denise
D
Horn
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Taroh
T
Kinoshita
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, 13353 Berlin, Germany; Berlin Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. Electronic address: peter.krawitz@charite.de.
Peter M
PM
Krawitz
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000469:Alkaline Phosphatase / Q000097:blood; D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People / Q000235:genetics; D016466:CHO Cells; D002265:Carboxylic Ester Hydrolases; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003241:Consanguinity; D006224:Cricetinae; D003412:Cricetulus; D059472:Exome; D005260:Female; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010154:Pakistan; D010375:Pedigree; D010760:Phosphorus Metabolism Disorders / Q000235:genetics* / Q000473:pathology; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012529:Saudi Arabia; D014481:United States; D044465:White People / Q000235:genetics
D011956:Receptors, Cell Surface; D002265:Carboxylic Ester Hydrolases; C476212:PGAP3 protein, human; D000469:Alkaline Phosphatase