Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy

Thi Tuyet Mai Nguyen, Yoshiko Murakami, Sabrina Mobilio, Marcello Niceta, Giuseppe Zampino, Christophe Philippe, Sébastien Moutton, Maha S. Zaki, Kiely N. James, Damir Musaev, Weiyi Mu, Kristin Baranano, Jessica R. Nance, Jill A. Rosenfeld, Nancy Braverman, Andrea Ciolfi, Francisca Millan, Richard E. Person, Ange-Line Bruel, Christel Thauvin-RobinetAthina Ververi, Catherine Devile, Alison Male, Stephanie Efthymiou, Reza Maroofian, Henry Houlden, Shazia Maqbool, Fatima Rahman, Nissan V. Baratang, Justine Rousseau, Anik St-Denis, Matthew J. Elrick, Irina Anselm, Lance H. Rodan, Marco Tartaglia, Joseph Gleeson, Taroh Kinoshita, Philippe M. Campeau

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

4 Citazioni (Scopus)


Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.
Lingua originaleEnglish
pagine (da-a)484-495
Numero di pagine12
RivistaAmerican Journal of Human Genetics
Stato di pubblicazionePubblicato - 2020


  • Abnormalities, Multiple
  • Acyltransferases
  • Alleles
  • Cell Adhesion Molecules
  • Cerebellar Diseases
  • Epilepsy
  • Female
  • GPI8
  • Genetic Variation
  • Humans
  • Intellectual Disability
  • Male
  • Muscle Hypotonia
  • Nervous System Malformations
  • Neurodevelopmental Disorders
  • PIGK
  • Pedigree
  • Syndrome
  • glycosylphosphatidylinositol (GPI)
  • inherited GPI deficiency disorders (IGDs)
  • transamidase


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