2. Academic Validation
  3. Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies

Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies

  • Am J Hum Genet. 2019 Aug 1;105(2):395-402. doi: 10.1016/j.ajhg.2019.06.009.
Alexej Knaus 1,  Fanny Kortüm 2,  Tjitske Kleefstra 3,  Asbjørg Stray-Pedersen 4,  Dejan Đukić 5,  Yoshiko Murakami 6,  Thorsten Gerstner 7,  Hans van Bokhoven 3,  Zafar Iqbal 8,  Denise Horn 9,  Taroh Kinoshita 6,  Maja Hempel 2,  Peter M Krawitz 5
Affiliations

Affiliations

  • 1 Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany. Electronic address: [email protected].
  • 2 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 3 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 4 Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, 0424 Oslo, Norway.
  • 5 Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany.
  • 6 Research Institute for Microbial Diseases and World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
  • 7 Department of Pediatrics, Sørlandet Hospital, 4838 Arendal, Norway.
  • 8 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Neurology, Oslo University Hospital, 0424 Oslo, Norway.
  • 9 Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
PMID: 31353022 DOI: 10.1016/j.ajhg.2019.06.009
Abstract

The glycosylphosphatidylinositol (GPI) anchor links over 150 proteins to the cell surface and is present on every cell type. Many of these proteins play crucial roles in neuronal development and function. Mutations in 18 of the 29 genes implicated in the biosynthesis of the GPI anchor have been identified as the cause of GPI biosynthesis deficiencies (GPIBDs) in humans. GPIBDs are associated with intellectual disability and seizures as their cardinal features. An essential component of the GPI transamidase complex is PIGU, along with PIGK, PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI anchor in the endoplasmic reticulum (ER). Here, we report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in five individuals from three unrelated families. All individuals presented with global developmental delay, severe-to-profound intellectual disability, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Using multicolor flow cytometry, we determined a characteristic profile for GPI transamidase deficiency. On granulocytes this profile consisted of reduced cell-surface expression of fluorescein-labeled proaerolysin (FLAER), CD16, and CD24, but not of CD55 and CD59; additionally, B cells showed an increased expression of free GPI anchors determined by T5 antibody. Moreover, computer-assisted facial analysis of different GPIBDs revealed a characteristic facial gestalt shared among individuals with mutations in PIGU and GPAA1. Our findings improve our understanding of the role of the GPI transamidase complex in the development of nervous and skeletal systems and expand the clinical spectrum of disorders belonging to the group of inherited GPI-anchor deficiencies.

Keywords

GPIBD; PIGU; automated facial analysis; deep phenotyping; epilepsy; glycosylphosphatidylinositol; inherited GPI deficiency; multicolor flow cytometry.

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